CoChat
Sign Up
Cited by 63Parkinson's Disease Mechanisms and TreatmentsNuclear Receptors and SignalingNeuroinflammation and Neurodegeneration Mechanisms

The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson’s Disease Pathogenesis

Open access
Ruiz-Pozo, Viviana A., Tamayo-Trujillo, Rafael, Cadena-Ullauri, Santiago, Frias-Toral, Evelyn, Guevara-Ramírez, Patricia, Paz-Cruz, Elius, Chapela, Sebastián, Montalván, Martha +3 more·2023·Nutrients
DOI 10.3390/nu15163585PMC PMC10458139
Open this paper in CoChat — free accountOpen PDF

Abstract

Parkinson’s disease (PD) is a degenerative condition resulting from the loss of dopaminergic neurons. This neuronal loss leads to motor and non-motor neurological symptoms. Most PD cases are idiopathic, and no cure is available. Recently, it has been proposed that insulin resistance (IR) could be a central factor in PD development. IR has been associated with PD neuropathological features like α-synuclein aggregation, dopaminergic neuronal loss, neuroinflammation, mitochondrial dysfunction, and autophagy. These features are related to impaired neurological metabolism, neuronal death, and the aggravation of PD symptoms. Moreover, pharmacological options that involve insulin signaling improvement and dopaminergic and non-dopaminergic strategies have been under development. These drugs could prevent the metabolic pathways involved in neuronal damage. All these approaches could improve PD outcomes. Also, new biomarker identification may allow for an earlier PD diagnosis in high-risk individuals. This review describes the main pathways implicated in PD development involving IR. Also, it presents several therapeutic options that are directed at insulin signaling improvement and could be used in PD treatment. The understanding of IR molecular mechanisms involved in neurodegenerative development could enhance PD therapeutic options and diagnosis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/nu15163585

Cites

20 of 20 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Dysbiosis caused by dietary changes, antibiotic exposure, or chronic illness may disrupt production of compounds such as serotonin or GABA, potentially impacting appetite, food intake, mood, anxiety, or depression.

    “Although still emerging, this field suggests that dysbiosis caused by dietary changes, antibiotic exposure, or chronic illness may disrupt the production of compounds such as serotonin or GABA, potentially impacting appetite, food intake, mood, anxiety, or depression [91,92].”

    From The Seven Methods for the Evaluation of Nutritional Status—ABCDEFG: Narrative Review (2026) · cites this paper as [92]

    The Discussion (page unavailable) says intestinal microbiota may mediate neuroinflammation in Parkinson’s disease and links impaired dopamine signaling to depression and anxiety. It does not connect dysbiosis from diet, antibiotics, or chronic illness to serotonin or GABA production, appetite, or food intake; searches for those terms did not locate that mechanism in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 140

  1. [1]Cao P. Abedini A. Raleigh D.P. Aggregation of islet amyloid polypeptide: From physical chemistry to cell biology Curr. Opin. Struct. Biol. 2013 23 82 89 10.1016/j.sbi.2012.11.003 23266002 PMC3969731 · DOI
  2. [4]Geng X. Lou H. Wang J. Li L. Swanson A.L. Sun M. Beers-Stolz D. Watkins S. Perez R.G. Drain P. α-synuclein binds the KATP channel at insulin-secretory granules and inhibits insulin secretion Am. J. Physiol. -Endocrinol. Metab. 2011 300 276 286 10.1152/ajpendo.00262.2010 20858756 PMC4459921 · DOI
  3. [5]Athauda D. Foltynie T. Insulin resistance and Parkinson’s disease: A new target for disease modification? Prog. Neurobiol. 2016 145–146 98 120 10.1016/j.pneurobio.2016.10.001 27713036 · DOI
  4. [6]Maciejczyk M. Żebrowska E. Chabowski A. Insulin resistance and oxidative stress in the brain: What’s new? Int. J. Mol. Sci. 2019 20 874 10.3390/ijms20040874 30781611 PMC6413037 · DOI
  5. [7]Svenningsson P. Wirdefeldt K. Yin L. Fang F. Markaki I. Efendic S. Ludvigsson J.F. Reduced incidence of Parkinson’s disease after dipeptidyl peptidase-4 inhibitors—A nationwide case-control study Mov. Disord. 2016 31 1422 1423 10.1002/mds.26734 27431803 · DOI
  6. [8]Badawi G.A. Abd El Fattah M.A. Zaki H.F. El Sayed M.I. Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson’s disease Inflammopharmacology 2017 25 369 382 10.1007/s10787-017-0331-6 28258522 · DOI
  7. [9]Ou Z. Pan J. Tang S. Duan D. Yu D. Nong H. Wang Z. Global Trends in the Incidence, Prevalence, and Years Lived With Disability of Parkinson’s Disease in 204 Countries/Territories From 1990 to 2019 Front. Public Health 2021 9 776847 10.3389/fpubh.2021.776847 34950630 PMC8688697 · DOI
  8. [11]Llibre-Guerra J.J. Prina M. Sosa A.L. Acosta D. Jimenez-Velazquez I.Z. Guerra M. Salas A. Llibre-Guerra J.C. Valvuerdi A. Peeters G. Prevalence of parkinsonism and Parkinson disease in urban and rural populations from Latin America: A community based study Lancet Reg. Health Am. 2022 7 100136 10.1016/j.lana.2021.100136 35300390 PMC8920908 · DOI
  9. [12]Brakedal B. Toker L. Haugarvoll K. Tzoulis C. A nationwide study of the incidence, prevalence and mortality of Parkinson’s disease in the Norwegian population npj Park. Dis. 2022 8 19 10.1038/s41531-022-00280-4 35236852 PMC8891365 · DOI
  10. [13]Tansey M.G. Wallings R.L. Houser M.C. Herrick M.K. Keating C.E. Joers V. Inflammation and immune dysfunction in Parkinson disease Nat. Rev. Immunol. 2022 22 657 673 10.1038/s41577-022-00684-6 35246670 PMC8895080 · DOI · Paper page
  11. [14]Lee H.M. Koh S.-B. Many Faces of Parkinson’s Disease: Non-Motor Symptoms of Parkinson’s Disease J. Mov. Disord. 2015 8 92 97 10.14802/jmd.15003 26090081 PMC4460545 · DOI · Paper page
  12. [15]Dahbour S.S. Al Murr M.J. Oweis L.H. Al Antary N.T. Mohsen M. Al Fegi S. Non-motor manifestation of Parkinson’s disease: A cross-sectional study in a teaching hospital in Jordan Egypt. J. Neurol. Psychiatry Neurosurg. 2022 58 148 10.1186/s41983-022-00559-6 · DOI
  13. [16]Lindqvist D. Kaufman E. Brundin L. Hall S. Surova Y. Hansson O. Non-Motor Symptoms in Patients with Parkinson’s Disease—Correlations with Inflammatory Cytokines in Serum PLoS ONE 2012 7 e47387 10.1371/journal.pone.0047387 23082161 PMC3474801 · DOI · Paper page
  14. [17]Crosiers D. Santens P. Chaudhuri K.R. Editorial: Prodromal Parkinson’s Disease Front. Neurol. 2021 11 1 6 10.3389/fneur.2020.634490 PMC7873967 33584526 · DOI
  15. [18]Savica R. Carlin J.M. Grossardt B.R. Bower J.H. Ahlskog J.E. Maraganore D.M. Bharucha A.E. Rocca W.A. Medical records documentation of constipation preceding Parkinson disease: A case-control study Neurology 2009 73 1752 1758 10.1212/WNL.0b013e3181c34af5 19933976 PMC2788809 · DOI
  16. [19]Postuma R.B. Prodromal Parkinson disease: Do we miss the signs? Nat. Rev. Neurol. 2019 15 437 438 10.1038/s41582-019-0215-z 31152151 · DOI
  17. [20]Ball N. Teo W.P. Chandra S. Chapman J. Parkinson’s disease and the environment Front. Neurol. 2019 10 218 10.3389/fneur.2019.00218 30941085 PMC6433887 · DOI
  18. [21]Pillay N.S. Ross O.A. Christoffels A. Bardien S. Current Status of Next-Generation Sequencing Approaches for Candidate Gene Discovery in Familial Parkinson’s Disease Front. Genet. 2022 13 781816 10.3389/fgene.2022.781816 35299952 PMC8921601 · DOI
  19. [22]Simon D.K. Tanner C.M. Brundin P. Parkinson Disease Epidemiology, Pathology, Genetics and Pathophysiology Clin. Geriatr. Med. 2020 36 1 12 10.1016/j.cger.2019.08.002 31733690 PMC6905381 · DOI · Paper page
  20. [23]Polymeropoulos M.H. Lavedan C. Leroy E. Ide S.E. Dehejia A. Dutra A. Pike B. Root H. Rubenstein J. Boyer R. Mutation in the α-synuclein gene identified in families with Parkinson’s disease Science 1997 276 2045 2047 10.1126/science.276.5321.2045 9197268 · DOI · Paper page
  21. [24]Pang S.Y.Y. Ho P.W.L. Liu H.F. Leung C.T. Li L. Chang E.E.S. Ramsden D.B. Ho S.L. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease Transl. Neurodegener. 2019 8 23 10.1186/s40035-019-0165-9 31428316 PMC6696688 · DOI
  22. [25]Kouli A. Torsney K.M. Kuan W.-L. Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis Stoker T.B. Greenland J.C. Exon Publications Brisbane, Australia 2018 30702842
  23. [27]Tan E.K. Chao Y.X. West A. Chan L.L. Poewe W. Jankovic J. Parkinson disease and the immune system—Associations, mechanisms and therapeutics Nat. Rev. Neurol. 2020 16 303 318 10.1038/s41582-020-0344-4 32332985 · DOI · Paper page
  24. [28]Dierssen M. Barone E. Editorial: Brain Insulin Resistance in Neurodevelopmental and Neurodegenerative Disorders: Mind the Gap! Front. Neurosci. 2021 15 730378 10.3389/fnins.2021.730378 34447295 PMC8382942 · DOI
  25. [30]Kannarkat G.T. Cook D.A. Lee J.K. Chang J. Chung J. Sandy E. Paul K.C. Ritz B. Bronstein J. Factor S.A. Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: An observational and case-control study Parkinson’s Dis. 2015 1 15002 10.1038/npjparkd.2015.2 PMC4853162 27148593 · DOI
  26. [32]Perruolo G. Viggiano D. Fiory F. Cassese A. Nigro C. Liotti A. Miele C. Beguinot F. Formisano P. Parkinson-like phenotype in insulin-resistant PED/PEA-15 transgenic mice Sci. Rep. 2016 6 29967 10.1038/srep29967 27426254 PMC4947959 · DOI
  27. [33]Charvin D. Medori R. Hauser R.A. Rascol O. Therapeutic strategies for Parkinson disease: Beyond dopaminergic drugs Nat. Rev. Drug Discov. 2018 17 804 822 10.1038/nrd.2018.136 30262889 · DOI
  28. [34]Poewe W. Seppi K. Tanner C.M. Halliday G.M. Brundin P. Volkmann J. Schrag A.E. Lang A.E. Parkinson disease Nat. Rev. Dis. Prim. 2017 3 17013 10.1038/nrdp.2017.13 28332488 · DOI · Paper page
  29. [35]Takamatsu Y. Ho G. Koike W. Sugama S. Takenouchi T. Waragai M. Wei J. Sekiyama K. Hashimoto M. Combined immunotherapy with “anti-insulin resistance” therapy as a novel therapeutic strategy against neurodegenerative diseases npj Park. Dis. 2017 3 4 10.1038/s41531-016-0001-1 28649604 PMC5445606 · DOI
  30. [36]Sharma T. Kaur D. Grewal A.K. Singh T.G. Therapies modulating insulin resistance in Parkinson’s disease: A cross talk Neurosci. Lett. 2021 749 135754 10.1016/j.neulet.2021.135754 33610666 · DOI · Paper page
  31. [37]Bianchi V.E. Herrera P.F. Laura R. Bianchi V.E. Effect of nutrition on neurodegenerative diseases. A systematic review E ff ect of nutrition on neurodegenerative diseases. A systematic review Nutr. Neurosci. 2019 24 810 834 10.1080/1028415X.2019.1681088 31684843 · DOI
  32. [38]Knight E. Geetha T. Burnett D. Babu J.R. The Role of Diet and Dietary Patterns in Parkinson’s Disease Nutrients 2022 14 4472 10.3390/nu14214472 36364733 PMC9654624 · DOI
  33. [39]Hölscher C. Brain insulin resistance: Role in neurodegenerative disease and potential for targeting Expert Opin. Investig. Drugs 2020 29 333 348 10.1080/13543784.2020.1738383 32175781 · DOI · Paper page
  34. [40]Bosco D. Plastino M. Cristiano D. Colica C. Ermio C. De Bartolo M. Mungari P. Fonte G. Consoli D. Consoli A. Dementia is associated with insulin resistance in patients with Parkinson’s disease J. Neurol. Sci. 2012 315 39 43 10.1016/j.jns.2011.12.008 22265943 · DOI
  35. [41]Femminella G.D. Livingston N.R. Raza S. van der Doef T. Frangou E. Love S. Busza G. Calsolaro V. Carver S. Holmes C. Does insulin resistance influence neurodegeneration in non-diabetic Alzheimer’s subjects? Alzheimer’s Res. Ther. 2021 13 47 10.1186/s13195-021-00784-w 33597002 PMC7890851 · DOI
  36. [42]Cheong J.L.Y. de Pablo-Fernandez E. Foltynie T. Noyce A.J. The Association Between Type 2 Diabetes Mellitus and Parkinson’s Disease J. Parkinson’s Dis. 2020 10 775 789 10.3233/JPD-191900 32333549 PMC7458510 · DOI
  37. [43]Shaughness M. Acs D. Brabazon F. Hockenbury N. Byrnes K.R. Role of Insulin in Neurotrauma and Neurodegeneration: A Review Front. Neurosci. 2020 14 547175 10.3389/fnins.2020.547175 33100956 PMC7546823 · DOI
  38. [44]Vidović M. Rikalovic M.G. Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches Cells 2022 11 1732 10.3390/cells11111732 35681426 PMC9179656 · DOI
  39. [45]Magistrelli L. Contaldi E. Comi C. The impact of snca variations and its product alpha-synuclein on non-motor features of parkinson’s disease Life 2021 11 804 10.3390/life11080804 34440548 PMC8401994 · DOI
  40. [46]Singleton A.B. Farrer M. Johnson J. Singleton A. Hague S. Kachergus J. Hulihan M. Peuralinna T. Dutra A. Nussbaum R. α-Synuclein Locus Triplication Causes Parkinson’s Disease Science 2003 302 841 10.1126/science.1090278 14593171 · DOI · Paper page
  41. [47]Giorgetti S. Greco C. Tortora P. Aprile F.A. Targeting amyloid aggregation: An overview of strategies and mechanisms Int. J. Mol. Sci. 2018 19 2677 10.3390/ijms19092677 30205618 PMC6164555 · DOI
  42. [48]Fujiwara H. Hasegawa M. Dohmae N. Kawashima A. Masliah E. Goldberg M.S. Shen J. Takio K. Iwatsubo T. α-synuclein is phosphorylated in synucleinopathy lesions Nat. Cell Biol. 2002 4 160 164 10.1038/ncb748 11813001 · DOI
  43. [49]Barrett P.J. Timothy Greenamyre J. Post-translational modification of α-synuclein in Parkinson’s disease Brain Res. 2015 1628 247 253 10.1016/j.brainres.2015.06.002 26080075 · DOI
  44. [50]Du X. Xie X. Liu R. The Role of α-Synuclein Oligomers in Parkinson’s Disease Int. J. Mol. Sci. 2020 21 8645 10.3390/ijms21228645 33212758 PMC7697105 · DOI
  45. [51]Danzer K.M. Krebs S.K. Wolff M. Birk G. Hengerer B. Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology J. Neurochem. 2009 111 192 203 10.1111/j.1471-4159.2009.06324.x 19686384 · DOI
  46. [52]Jaikaran E.T.A.S. Nilsson M.R. Clark A. Pancreatic β-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation Biochem. J. 2004 377 709 716 10.1042/bj20030852 14565847 PMC1223903 · DOI
  47. [53]Gómez-Benito M. Granado N. García-Sanz P. Michel A. Dumoulin M. Moratalla R. Modeling Parkinson’s Disease With the Alpha-Synuclein Protein Front. Pharmacol. 2020 11 356 10.3389/fphar.2020.00356 32390826 PMC7191035 · DOI
  48. [54]Zhang G. Xia Y. Wan F. Ma K. Guo X. Kou L. Yin S. Han C. Liu L. Huang J. New Perspectives on Roles of Alpha-Synuclein in Parkinson’s Disease Front. Aging Neurosci. 2018 10 370 10.3389/fnagi.2018.00370 30524265 PMC6261981 · DOI
  49. [55]Shieh J.C.C. Huang P.T. Lin Y.F. Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies Mol. Neurobiol. 2020 57 1966 1977 10.1007/s12035-019-01858-5 31900863 · DOI
  50. [56]Watson G.S. Leverenz J.B. Profile of cognitive impairment in parkinson’s disease Brain Pathol. 2010 20 640 645 10.1111/j.1750-3639.2010.00373.x 20522089 PMC3049172 · DOI
  51. [57]Green H. Tsitsi P. Markaki I. Aarsland D. Svenningsson P. Novel Treatment Opportunities Against Cognitive Impairment in Parkinson’s Disease with an Emphasis on Diabetes-Related Pathways CNS Drugs 2019 33 143 160 10.1007/s40263-018-0601-x 30687888 PMC6373401 · DOI
  52. [58]Bergeron M. Motter R. Tanaka P. Fauss D. Babcock M. Chiou S.S. Nelson S. San Pablo F. Anderson J.P. In vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 α-synuclein phosphorylation in mouse brain Neuroscience 2014 256 72 82 10.1016/j.neuroscience.2013.09.061 24128992 · DOI
  53. [59]Zhang C. Ni C. Lu H. Polo-Like Kinase 2: From Principle to Practice Front. Oncol. 2022 12 956225 10.3389/fonc.2022.956225 35898867 PMC9309260 · DOI
  54. [60]Yang L. Wang H. Liu L. Xie A. The role of insulin/IGF-1/PI3K/Akt/GSK3β signaling in parkinson’s disease dementia Front. Neurosci. 2018 12 73 10.3389/fnins.2018.00073 29515352 PMC5826217 · DOI
  55. [63]Bingham E.M. Hopkins D. Smith D. Pernet A. Hallett W. Reed L. Marsden P.K. Amiel S.A. The role of insulin in human brain glucose metabolism: An 18fluoro-deoxyglucose positron emission tomography study Diabetes 2002 51 3384 3390 10.2337/diabetes.51.12.3384 12453890 · DOI
  56. [64]Fiory F. Perruolo G. Cimmino I. Cabaro S. Pignalosa F.C. Miele C. Beguinot F. Formisano P. Oriente F. The Relevance of Insulin Action in the Dopaminergic System Front. Neurosci. 2019 13 868 10.3389/fnins.2019.00868 31474827 PMC6706784 · DOI
  57. [65]Ramalingam M. Kim S.J. The Neuroprotective Role of Insulin Against MPP+-Induced Parkinson’s Disease in Differentiated SH-SY5Y Cells J. Cell. Biochem. 2016 117 917 926 10.1002/jcb.25376 26364587 · DOI
  58. [66]Chong Z.Z. Shang Y.C. Wang S. Maiese K. A critical kinase cascade in neurological disorders: PI3K, Akt and mTOR Future Neurol. 2012 7 733 748 10.2217/fnl.12.72 23144589 PMC3491909 · DOI
  59. [67]Long H.Z. Cheng Y. Zhou Z.W. Luo H.Y. Wen D.D. Gao L.C. 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 10.3389/fphar.2021.648636 33935751 PMC8082498 · DOI
  60. [68]Wang Y. Liu W. He X. Zhou F. Parkinson’s disease-associated Dj-1 mutations increase abnormal phosphorylation of tau protein through Akt/Gsk-3β pathways J. Mol. Neurosci. 2013 51 911 918 10.1007/s12031-013-0099-0 23979838 · DOI
  61. [69]Costes S. Huang C.J. Gurlo T. Daval M. Matveyenko A.V. Rizza R.A. Butler A.E. Butler P.C. β-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency Diabetes 2011 60 227 238 10.2337/db10-0522 20980462 PMC3012175 · DOI
  62. [70]Schmidt M.F. Gan Z.Y. Komander D. Dewson G. Ubiquitin signalling in neurodegeneration: Mechanisms and therapeutic opportunities Cell Death Differ. 2021 28 570 590 10.1038/s41418-020-00706-7 33414510 PMC7862249 · DOI
  63. [71]McNaught K.S.P. Jenner P. Proteasomal function is impaired in substantia nigra in Parkinson’s disease Neurosci. Lett. 2001 297 191 194 10.1016/S0304-3940(00)01701-8 11137760 · DOI · Paper page
  64. [72]Yang X.D. Xiang D.X. Yang Y.Y. Role of E3 ubiquitin ligases in insulin resistance Diabetes Obes. Metab. 2016 18 747 754 10.1111/dom.12677 27097743 · DOI
  65. [73]Dehay B. Bové J. Rodríguez-Muela N. Perier C. Recasens A. Boya P. Vila M. Pathogenic lysosomal depletion in Parkinson’s disease J. Neurosci. 2010 30 12535 12544 10.1523/JNEUROSCI.1920-10.2010 20844148 PMC6633458 · DOI · Paper page
  66. [74]Singh S.S. Rai S.N. Birla H. Zahra W. Rathore A.S. Singh S.P. NF-κB-Mediated Neuroinflammation in Parkinson’s Disease and Potential Therapeutic Effect of Polyphenols Neurotox. Res. 2020 37 491 507 10.1007/s12640-019-00147-2 31823227 · DOI
  67. [75]Perry V.H. Innate inflammation in Parkinson’s disease Cold Spring Harb. Perspect. Med. 2012 2 a009373 10.1101/cshperspect.a009373 22951445 PMC3426823 · DOI
  68. [76]Kam T. Hinkle J.T. Dawson T.M. Dawson V.L. Microglia and Astrocyte Dysfunction in Parkinson’s Disease Tae-In Neurobiol. Dis. 2020 144 105028 10.1016/j.nbd.2020.105028 32736085 PMC7484088 · DOI
  69. [77]Araújo B. Caridade-Silva R. Soares-Guedes C. Martins-Macedo J. Gomes E.D. Monteiro S. Teixeira F.G. Neuroinflammation and Parkinson’s Disease—From Neurodegeneration to Therapeutic Opportunities Cells 2022 11 2908 10.3390/cells11182908 36139483 PMC9497016 · DOI
  70. [78]Grotemeyer A. McFleder R.L. Wu J. Wischhusen J. Ip C.W. Neuroinflammation in Parkinson’s Disease—Putative Pathomechanisms and Targets for Disease-Modification Front. Immunol. 2022 13 878771 10.3389/fimmu.2022.878771 35663989 PMC9158130 · DOI
  71. [79]Glezer I. Simard A.R. Rivest S. Neuroprotective role of the innate immune system by microglia Neuroscience 2007 147 867 883 10.1016/j.neuroscience.2007.02.055 17459594 · DOI · Paper page
  72. [80]Salter M.W. Stevens B. Microglia emerge as central players in brain disease Nat. Med. 2017 23 1018 1027 10.1038/nm.4397 28886007 · DOI · Paper page
  73. [81]Nagatsu T. Mogi M. Ichinose H. Togari A. Cytokines in Parkinson’s disease J. Neural Transm. Suppl. 2000 58 143 151 11128604
  74. [82]Harms A.S. Ferreira S.A. Romero-Ramos M. Periphery and brain, innate and adaptive immunity in Parkinson’s disease Acta Neuropathol. 2021 141 527 545 10.1007/s00401-021-02268-5 33555429 PMC7952334 · DOI
  75. [83]Schonhoff A.M. Williams G.P. Wallen Z.D. Standaert D.G. Harms A.S. Innate and adaptive immune responses in Parkinson’s disease Prog. Brain Res. 2020 252 169 216 10.1016/bs.pbr.2019.10.006 32247364 PMC7185735 · DOI
  76. [84]Brochard V. Combadière B. Prigent A. Laouar Y. Perrin A. Beray-Berthat V. Bonduelle O. Alvarez-Fischer D. Callebert J. Launay J.M. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease J. Clin. Investig. 2009 119 182 192 10.1172/JCI36470 19104149 PMC2613467 · DOI · Paper page
  77. [86]Yoon S. Oh Y.J. Glucose Levels in Culture Medium Determine Cell Death Mode in MPP+-treated Dopaminergic Neuronal Cells Exp. Neurobiol. 2015 24 197 205 10.5607/en.2015.24.3.197 26412968 PMC4580746 · DOI
  78. [87]Çınar E. Tel B.C. Şahin G. Neuroinflammation in Parkinson’s Disease and its Treatment Opportunities Balk. Med. J. 2022 39 318 333 10.4274/balkanmedj.galenos.2022.2022-7-100 36036436 PMC9469676 · DOI
  79. [88]Lee S. Hong D.G. Yang S. Kim J. Baek M. Kim S. Thirumalai D. Chung H.Y. Chang S. Lee J. Anti-Inflammatory Effect of IKK-Activated GSK-3 β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson’s Disease Int. J. Mol. Sci. 2022 23 998 10.3390/ijms23020998 35055183 PMC8779943 · DOI
  80. [89]Jha S.K. Jha N.K. Kumar D. Ambasta R.K. Kumar P. Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration Biochim. Biophys. Acta-Mol. Basis Dis. 2017 1863 1132 1146 10.1016/j.bbadis.2016.06.015 27345267 · DOI · Paper page
  81. [90]de Lara A.C.M. Interpreting the High Energy Consumption of the Brain at Rest Proceedings 2020 46 30 10.3390/ecea-5-06694 · DOI
  82. [91]Jung H. Kim S.Y. Canbakis Cecen F.S. Cho Y. Kwon S.K. Dysfunction of Mitochondrial Ca2+ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases Front. Cell Dev. Biol. 2020 8 599792 10.3389/fcell.2020.599792 33392190 PMC7775422 · DOI
  83. [93]Erustes A.G. D’Eletto M. Guarache G.C. Ureshino R.P. Bincoletto C. da Silva Pereira G.J. Piacentini M. Smaili S.S. Overexpression of α-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75–IP3R interaction J. Neurosci. Res. 2021 99 2932 2947 10.1002/jnr.24952 34510532 · DOI
  84. [95]Gao X.-Y. Yang T. Gu Y. Sun X.-H. Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy Front. Aging Neurosci. 2022 14 885500 10.3389/fnagi.2022.885500 35795234 PMC9250984 · DOI
  85. [96]Gureev A.P. Shaforostova E.A. Popov V.N. Regulation of mitochondrial biogenesis as a way for active longevity: Interaction between the Nrf2 and PGC-1α signaling pathways Front. Genet. 2019 10 435 10.3389/fgene.2019.00435 31139208 PMC6527603 · DOI
  86. [97]Hang L. Thundyil J. Lim K.L. Mitochondrial dysfunction and Parkinson disease: A Parkin–AMPK alliance in neuroprotection Ann. N. Y. Acad. Sci. 2015 1350 37 47 10.1111/nyas.12820 26121488 · DOI
  87. [98]Shin J.H. Ko H.S. Kang H. Lee Y. Lee Y.I. Pletinkova O. Troconso J.C. Dawson V.L. Dawson T.M. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in parkinson’s disease Cell 2011 144 689 702 10.1016/j.cell.2011.02.010 21376232 PMC3063894 · DOI · Paper page
  88. [99]Krzystek T.J. Falzone T.L. Swinter K. Differential mitochondrial roles for α-synuclein in DRP1-dependent fi ssion and PINK1/Parkin-mediated oxidation Cell Death Dis. 2021 12 796 10.1038/s41419-021-04046-3 34404758 PMC8371151 · DOI
  89. [100]Thorne N.J. Tumbarello D.A. The relationship of alpha-synuclein to mitochondrial dynamics and quality control Front. Mol. Neurosci. 2022 15 947191 10.3389/fnmol.2022.947191 36090250 PMC9462662 · DOI
  90. [101]Chinta S.J. Mallajosyula J.K. Rane A. Andersen J.K. Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo Neurosci. Lett. 2010 486 235 239 10.1016/j.neulet.2010.09.061 20887775 PMC2967673 · DOI
  91. [102]Butler E.K. Voigt A. Lutz A.K. Toegel J.P. Gerhardt E. Karsten P. The Mitochondrial Chaperone Protein TRAP1 Mitigates a—Synuclein Toxicity PLoS Genet. 2012 8 e1002488 10.1371/journal.pgen.1002488 22319455 PMC3271059 · DOI
  92. [103]Yu H. Sun T. He X. Wang Z. Zhao K. An J. Wen L. Li J.Y. Li W. Feng J. Association between Parkinson’s Disease and Diabetes Mellitus: From Epidemiology, Pathophysiology and Prevention to Treatment Aging Dis. 2022 13 1591 1605 10.14336/AD.2022.0325 36465171 PMC9662283 · DOI
  93. [104]Kim H. Lee J.Y. Park S.J. Kwag E. Kim J. Shin J.H. S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson’s Disease Model Cells 2022 11 3682 10.3390/cells11223682 36429110 PMC9688248 · DOI
  94. [105]Curry D.W. Stutz B. Andrews Z.B. Elsworth J.D. Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease J. Parkinson’s Dis. 2018 8 161 181 10.3233/JPD-171296 29614701 PMC6004921 · DOI
  95. [106]Sepúlveda D. Grunenwald F. Vidal A. Troncoso-Escudero P. Cisternas-Olmedo M. Villagra R. Vergara P. Aguilera C. Nassif M. Vidal R.L. Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson’s disease Sci. Rep. 2022 12 2038 10.1038/s41598-022-05941-1 35132125 PMC8821705 · DOI
  96. [107]Zhang H.Y. Jiang Y.C. Li J.R. Yan J.N. Wang X.J. Shen J.B. Ke K.F. Gu X.S. Neuroprotective effects of insulin-like growth factor-2 in 6-hydroxydopamine-induced cellular and mouse models of Parkinson’s disease Neural Regen. Res. 2023 18 1099 1106 10.4103/1673-5374.355815 36254999 PMC9827768 · DOI
  97. [109]Guillén C. Benito M. MTORC1 overactivation as a key aging factor in the progression to type 2 diabetes mellitus Front. Endocrinol. 2018 9 621 10.3389/fendo.2018.00621 PMC6198057 30386301 · DOI
  98. [110]Xilouri M. Stefanis L. Autophagic pathways in Parkinson disease and related disorders Expert Rev. Mol. Med. 2011 13 e8 10.1017/S1462399411001803 21418705 · DOI
  99. [111]De Mello N.P. Orellana A.M. Mazucanti C.H. De Morais Lima G. Scavone C. Kawamoto E.M. Insulin and autophagy in neurodegeneration Front. Neurosci. 2019 13 491 10.3389/fnins.2019.00491 31231176 PMC6558407 · DOI
  100. [112]Ning P. Jiang X. Yang J. Zhang J. Yang F. Cao H. Mitophagy: A potential therapeutic target for insulin resistance Front. Physiol. 2022 13 957968 10.3389/fphys.2022.957968 36082218 PMC9445132 · DOI
  101. [113]Barone E. Di Domenico F. Perluigi M. Butterfield D.A. The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease Free Radic. Biol. Med. 2021 176 16 33 10.1016/j.freeradbiomed.2021.09.006 34530075 PMC8595768 · DOI
  102. [114]Jiang T. Li G. Xu J. Gao S. Chen X. The Challenge of the Pathogenesis of Parkinson’s Disease: Is Autoimmunity the Culprit? Front. Immunol. 2018 9 2047 10.3389/fimmu.2018.02047 30319601 PMC6170625 · DOI
  103. [115]Müller T. Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease Expert Opin. Drug Metab. Toxicol. 2020 16 403 414 10.1080/17425255.2020.1750596 32238065 · DOI
  104. [117]Stansley B.J. Yamamoto B.K. L-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells Neuropharmacology 2013 67 243 251 10.1016/j.neuropharm.2012.11.010 23196068 PMC3638241 · DOI
  105. [118]Nowell J. Blunt E. Edison P. Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease Mol. Psychiatry 2023 28 217 229 10.1038/s41380-022-01792-4 36258018 PMC9812772 · DOI · Paper page
  106. [119]Bridges A. Bistas K.G. Jacobs T.F. Exenatide StatPearls Publishing St. Petersburg, FL, USA 2023 0203138708 30085523
  107. [120]Kastin A.J. Akerstrom V. Entry of exendin-4 into brain is rapid but may be limited at high doses Int. J. Obes. 2003 27 313 318 10.1038/sj.ijo.0802206 12629557 · DOI
  108. [121]Aviles-Olmos I. Dickson J. Kefalopoulou Z. Djamshidian A. Kahan J. Ell P. Whitton P. Wyse R. Isaacs T. Lees A. Motor and Cognitive Advantages Persist 12 Months after Exenatide Exposure in Parkinson’s Disease J. Parkinson’s Dis. 2015 4 337 344 10.3233/JPD-140364 24662192 · DOI
  109. [123]Perry T. Lahiri D.K. Chen D. Zhou J.I.E. Shaw K.T.Y. Egan J.M. Greig N.H. A novel neurothropic property of Glucagon-Like Peptide 1: A promoter of nerve growth factor-mediates differentiation in PC12 cells J. Pharmacol. Exp. Ther. 2002 300 958 966 10.1124/jpet.300.3.958 11861804 · DOI
  110. [126]McFarthing K. Larson D. Simuni T. Clinical Trial Highlights—GLP-1 agonists J. Parkinson’s Dis. 2020 10 355 368 10.3233/JPD-200002 32250322 PMC7242848 · DOI
  111. [127]Phung O.J. Scholle J.M. Talwar M. Coleman C.I. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes JAMA 2010 303 1410 1418 10.1001/jama.2010.405 20388897 · DOI · Paper page
  112. [128]Jeong S.H. Chung S.J. Yoo H.S. Hong N. Jung J.H. Baik K. Lee Y.H. Sohn Y.H. Lee P.H. Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson’s disease Brain 2021 144 1127 1137 10.1093/brain/awab015 33895825 · DOI
  113. [129]Gault V.A. Lennox R. Flatt P.R. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline Diabetes Obes. Metab. 2015 17 403 413 10.1111/dom.12432 25580570 · DOI
  114. [130]Lietzau G. Davidsson W. Östenson C.G. Chiazza F. Nathanson D. Pintana H. Skogsberg J. Klein T. Nyström T. Darsalia V. Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin Acta Neuropathol. Commun. 2018 6 14 10.1186/s40478-018-0517-1 29471869 PMC5824492 · DOI
  115. [131]Röhnert P. Schmidt W. Emmerlich P. Goihl A. Wrenger S. Bank U. Nordhoff K. Täger M. Ansorge S. Reinhold D. Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia J. Neuroinflamm. 2012 9 44 10.1186/1742-2094-9-44 PMC3359160 22373413 · DOI
  116. [132]Hang X.Z. Im A.K. Im S.K. Iu G.L. Ghrelin Modulates Insulin Sensitivity and Tau Phosphorylation in High Glucose-Induced Hippocampal Neurons Biol. Pharm. Bull. 2010 33 1165 1169 20606308
  117. [134]Russo C. Valle M.S. Russo A. The Interplay between Ghrelin and Microglia in Neuroinflammation: Implications for Obesity and Neurodegenerative Diseases Int. J. Mol. Sci. 2022 23 13432 10.3390/ijms232113432 36362220 PMC9654207 · DOI · Paper page
  118. [135]Wanneveich M. Moisan F. Jacqmin-Gadda H. Elbaz A. Joly P. Projections of prevalence, lifetime risk, and life expectancy of Parkinson’s disease (2010–2030) in France Mov. Disord. 2018 33 1449 1455 10.1002/mds.27447 30145805 · DOI
  119. [136]Yang W. Hamilton J.L. Kopil C. Beck J.C. Tanner C.M. Albin R.L. Ray Dorsey E. Dahodwala N. Cintina I. Hogan P. Current and projected future economic burden of Parkinson’s disease in the U.S npj Park. Dis. 2020 6 15 10.1038/s41531-020-0117-1 32665974 PMC7347582 · DOI · Paper page
  120. [137]Brunetti A. Foti D. Goldfine I.D. Identification of Unique Nuclear Regulatory Proteins for the Insulin Receptor Gene, Which Appear during Myocyte and Adipocyte Differentiation J. Clin. Investig. 1993 92 1288 1295 10.1172/JCI116702 8376587 PMC288270 · DOI
  121. [138]Brunetti A. Brunetti L. Foti D. Accili D. Goldfine I.D. Human Diabetes Associated with Defects in Nuclear Regulatory Proteins for the Insulin Receptor Gene J. Clin. Investig. 1996 97 258 262 10.1172/JCI118400 8550844 PMC507088 · DOI
  122. [139]Forloni G. Alpha Synuclein: Neurodegeneration and Inflammation Int. J. Mol. Sci. 2023 24 5914 10.3390/ijms24065914 36982988 PMC10059798 · DOI
  123. [140]Arotcarena M.L. Dovero S. Prigent A. Bourdenx M. Camus S. Porras G. Thiolat M.L. Tasselli M. Aubert P. Kruse N. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates Brain 2020 143 1462 1475 10.1093/brain/awaa096 32380543 · DOI · Paper page
  124. [142]Kim S. Kwon S.H. Kam T.I. Panicker N. Karuppagounder S.S. Lee S. Lee J.H. Kim W.R. Kook M. Foss C.A. Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease Neuron 2019 103 627–641.e7 10.1016/j.neuron.2019.05.035 PMC6706297 31255487 · DOI · Paper page
  125. [143]Romano S. Savva G.M. Bedarf J.R. Charles I.G. Hildebrand F. Narbad A. Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation npj Park. Dis. 2021 7 27 10.1038/s41531-021-00156-z PMC7946946 33692356 · DOI · Paper page
  126. [144]Sangwung P. Petersen K.F. Shulman G.I. Knowles J.W. Potential role of alterations in mitochondrial function in the pathogenesis of insulin resistance and type 2 diabetes Endocrinology 2021 161 bqaa017 10.1210/endocr/bqaa017 32060542 PMC7341556 · DOI
  127. [146]Fais M. Dore A. Galioto M. Galleri G. Crosio C. Iaccarino C. Parkinson’s disease-related genes and lipid alteration Int. J. Mol. Sci. 2021 22 7630 10.3390/ijms22147630 34299248 PMC8305702 · DOI
  128. [147]Estes R.E. Lin B. Khera A. Davis M.Y. Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo? Front. Mol. Neurosci. 2021 14 788695 10.3389/fnmol.2021.788695 34987360 PMC8721228 · DOI
  129. [148]Alecu I. Bennett S.A.L. Dysregulated lipid metabolism and its role in α-synucleinopathy in Parkinson’s disease Front. Neurosci. 2019 13 328 10.3389/fnins.2019.00328 31031582 PMC6470291 · DOI
  130. [149]Chegão A. Vicente Miranda H. Unveiling new secrets in Parkinson’s disease: The glycatome Behav. Brain Res. 2023 442 114309 10.1016/j.bbr.2023.114309 36706808 · DOI
  131. [150]Bernhard F.P. Heinzel S. Binder G. Weber K. Apel A. Roeben B. Deuschle C. Maechtel M. Heger T. Nussbaum S. Insulin-like growth factor 1 (IGF-1) in Parkinson’s disease: Potential as trait-, progression- and prediction marker and confounding factors PLoS ONE 2016 11 e0150552 10.1371/journal.pone.0150552 26967642 PMC4788352 · DOI
  132. [151]Sherbaf F.G. Mohajer B. Ashraf-Ganjouei A. Zadeh M.M. Javinani A. Moghaddam H.S. Shandiz M.S. Aarabi M.H. Serum insulin-like growth factor-1 in Parkinson’s disease; study of cerebrospinal fluid biomarkers and white matter microstructure Front. Endocrinol. 2018 9 608 10.3389/fendo.2018.00608 PMC6224341 30450079 · DOI
  133. [152]Sharma S.K. Chorell E. Steneberg P. Vernersson-Lindahl E. Edlund H. Wittung-Stafshede P. Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner Sci. Rep. 2015 5 12531 10.1038/srep12531 26228656 PMC4521159 · DOI
  134. [153]Merino B. Casanueva-Álvarez E. Quesada I. González-Casimiro C.M. Fernández-Díaz C.M. Postigo-Casado T. Leissring M.A. Kaestner K.H. Perdomo G. Cózar-Castellano I. Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation Diabetologia 2022 65 1375 1389 10.1007/s00125-022-05729-y 35652923 PMC9283140 · DOI
  135. [154]Wang S.Y. Wu S.L. Chen T.C. Chuang C. Sen Antidiabetic agents for treatment of parkinson’s disease: A meta-analysis Int. J. Environ. Res. Public Health 2020 17 4805 10.3390/ijerph17134805 32635358 PMC7369739 · DOI
  136. [157]Yazar V. Kang S.U. Ha S. Dawson V.L. Dawson T.M. Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPARγ associated gene regulation Sci. Rep. 2021 11 21500 10.1038/s41598-021-00858-7 34728675 PMC8563805 · DOI
  137. [158]Corona J.C. Duchen M.R. PPARγ and PGC-1α as Therapeutic Targets in Parkinson’s Neurochem. Res. 2015 40 308 316 10.1007/s11064-014-1377-0 25007880 PMC4326663 · DOI
  138. [159]Agostini F. Masato A. Bubacco L. Bisaglia M. Metformin repurposing for parkinson disease therapy: Opportunities and challenges Int. J. Mol. Sci. 2022 23 398 10.3390/ijms23010398 35008822 PMC8745385 · DOI
  139. [160]Lu M. Chen H. Nie F. Wei X. Tao Z. Ma J. The potential role of metformin in the treatment of Parkinson’s disease J. Bio-X Res. 2020 3 27 35 10.1097/JBR.0000000000000055 · DOI
  140. [161]Zambrano A.K. Cadena-Ullauri S. Guevara-Ramírez P. Frias-Toral E. Ruiz-Pozo V.A. Paz-Cruz E. Tamayo-Trujillo R. Montalvo M. Sarno G. Guerra C.V. The Impact of a Very-Low-Calorie Ketogenic Diet in the Gut Microbiota Composition in Obesity Nutrients 2023 15 2728 10.3390/nu15122728 37375632 PMC10305724 · DOI

Cited by

Sorted by citations

Authors
Ruiz-Pozo, V. A., Tamayo-Trujillo, R., Cadena-Ullauri, S., Frias-Toral, E., Guevara-Ramírez, P., Paz-Cruz, E., Chapela, S., Montalván, M., Morales-López, T., Simancas-Racines, D., & Zambrano, A. K.
Affiliations
  • Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
  • Universidad UTE (EC)
  • School of Medicine, Universidad Católica Santiago de Guayaquil, Guayaquil 090615, Ecuador
  • Universidad de Buenos Aires (AR)
  • Universidad Espíritu Santo (EC)
  • Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito 170527, Ecuador
Corresponding author
Zambrano, Ana Karina
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2023-08-15
Volume
15
Issue
16
Pages
3585
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu15163585
PMC
PMC10458139
OpenAlex
W4385839559
Cited by
63
References
20
Citations by year
2026: 13 · 2025: 29 · 2024: 20 · 2023: 1
FWCI
2.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Universidad UTE
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Parkinson's disease, insulin resistance, insulin signaling, dopaminergic neuron loss, alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy, neurodegeneration, biomarkers, Parkinson's disease treatment
MeSH terms
Autophagy, Dopamine, Humans, Insulin Resistance, Parkinson Disease, Cell Death, Insulins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review