Advertisement

CNS Drugs

, Volume 33, Issue 3, pp 209–223 | Cite as

Neuroprotective Actions of Glucagon-Like Peptide-1 (GLP-1) Analogues in Alzheimer’s and Parkinson’s Diseases

  • Andre F. Batista
  • Victor Bodart-Santos
  • Fernanda G. De FeliceEmail author
  • Sergio T. FerreiraEmail author
Leading Article

Abstract

The current absence of effective treatments for Alzheimer’s disease (AD) and Parkinson’s disease (PD) reflects an incomplete knowledge of the underlying disease processes. Considerable efforts have been made to investigate the central pathological features of these diseases, giving rise to numerous attempts to develop compounds that interfere with such features. However, further characterization of the molecular targets within the interconnected AD and PD pathways is still required. Impaired brain insulin signaling has emerged as a feature that contributes to neuronal dysfunction in both AD and PD, leading to strategies aiming at restoring this pathway in the brain. Long-acting glucagon-like peptide-1 (GLP-1) analogues marketed for treatment of type 2 diabetes mellitus have been tested and have shown encouraging protective actions in experimental models of AD and PD as well as in initial clinical trials. We review studies revealing the neuroprotective actions of GLP-1 analogues in pre-clinical models of AD and PD and promising results from recent clinical trials.

Notes

Acknowledgements

The authors acknowledge the use of Mind the Graph (http://www.mindthegraph.com) for the design of the figure in this work.

Compliance with Ethical Standards

Conflict of interest

AFB, VBS, FGDF and STF have no conflicts of interest that are directly relevant to the content of this article.

Funding

Work in the authors’ groups has been supported by the National Institute for Translational Neuroscience (Brazil), the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (to STF and FDF), and Alzheimer Society Canada and Weston Brain Institute (to FDF). AFB and VBS are supported by post-doctoral and pre-doctoral fellowships, respectively, from CNPq.

References

  1. 1.
    International Diabetes Federation. IDF Diabetes Atlas. 7th ed. Brussels: International Diabetes Federation; 2015.Google Scholar
  2. 2.
    United Nations, Department of Economic and Social Affairs, population division 2015. World population propects: the 2015 revision, key findings and advance tables.Google Scholar
  3. 3.
    Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348(14):1356–64.Google Scholar
  4. 4.
    Athauda D, Foltynie T. Challenges in detecting disease modification in Parkinson’s disease clinical trials. Parkinsonism Relat Disord. 2016;32:1–11.Google Scholar
  5. 5.
    Selkoe DJ. Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med. 2011;17(9):1060–5.Google Scholar
  6. 6.
    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(3):168–81.Google Scholar
  7. 7.
    Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson’s disease, insulin resistance and novel agents of neuroprotection. Brain. 2013;136(Pt 2):374–84.Google Scholar
  8. 8.
    Foltynie T, Kahan J. Parkinson’s disease: an update on pathogenesis and treatment. J Neurol. 2013;260(5):1433–40.Google Scholar
  9. 9.
    Holscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer’s and Parkinson’s disease models. Neuropharmacology. 2018;136(Pt B):251–259.Google Scholar
  10. 10.
    De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. 2014;63(7):2262–72.Google Scholar
  11. 11.
    Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement. 2014;10(1 Suppl):S76–83.Google Scholar
  12. 12.
    Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806.Google Scholar
  13. 13.
    Ward CW, Menting JG, Lawrence MC. The insulin receptor changes conformation in unforeseen ways on ligand binding: sharpening the picture of insulin receptor activation. Bioessays. 2013;35(11):945–54.  https://doi.org/10.1002/bies.201370111.Google Scholar
  14. 14.
    Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, et al. How insulin engages its primary binding site on the insulin receptor. Nature. 2013;493(7431):241–5.Google Scholar
  15. 15.
    Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013;47(1):145–71.Google Scholar
  16. 16.
    Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol. 2018;19(1):31–44.Google Scholar
  17. 17.
    Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7(2):85–96.Google Scholar
  18. 18.
    Banks WA, Jaspan JB, Huang W, Kastin AJ. Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides. 1997;18(9):1423–9.Google Scholar
  19. 19.
    Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.Google Scholar
  20. 20.
    Ferrario CR, Reagan LP. Insulin-mediated synaptic plasticity in the CNS: anatomical, functional and temporal contexts. Neuropharmacology. 2017;Dec:5.Google Scholar
  21. 21.
    Gray SM, Meijer RI, Barrett EJ. Insulin regulates brain function, but how does it get there? Diabetes. 2014;63(12):3992–7.Google Scholar
  22. 22.
    Erbsloh F, Bernsmeier A, Hillesheim H. The glucose consumption of the brain and its dependence on the liver. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr. 1958;196(6):611–26.Google Scholar
  23. 23.
    Debons AF, Krimsky I, From A, Cloutier RJ. Rapid effects of insulin on the hypothalamic satiety center. Am J Physiol. 1969;217(4):1114–8.Google Scholar
  24. 24.
    Thon M, Hosoi T, Ozawa K. Possible integrative actions of leptin and insulin signaling in the hypothalamus targeting energy homeostasis. Front Endocrinol (Lausanne). 2016;7:138.Google Scholar
  25. 25.
    Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272(5656):827–9.Google Scholar
  26. 26.
    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(4):1562–70.Google Scholar
  27. 27.
    Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem. 1999;274(49):34893–902.Google Scholar
  28. 28.
    Wickelgren I. Tracking insulin to the mind. Science. 1998;280(5363):517–9.Google Scholar
  29. 29.
    Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16(11):660–71.Google Scholar
  30. 30.
    Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708–19.Google Scholar
  31. 31.
    Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64(11):3927–36.Google Scholar
  32. 32.
    Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology. 1999;53(9):1937–42.Google Scholar
  33. 33.
    Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY. Risk of Alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiology. 2012;38(4):237–44.Google Scholar
  34. 34.
    Yang YW, Hsieh TF, Li CI, Liu CS, Lin WY, Chiang JH, et al. Increased risk of Parkinson disease with diabetes mellitus in a population-based study. Medicine (Baltimore). 2017;96(3):e5921.Google Scholar
  35. 35.
    Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O’Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol. 1997;145(4):301–8.Google Scholar
  36. 36.
    Pagano G, Polychronis S, Wilson H, Giordano B, Ferrara N, Niccolini F, et al. Diabetes mellitus and Parkinson disease. Neurology. 2018;90(19):e1654–62.Google Scholar
  37. 37.
    De Pablo-Fernandez E, Goldacre R, Pakpoor J, Noyce AJ, Warner TT. Association between diabetes and subsequent Parkinson disease: a record-linkage cohort study. Neurology. 2018;91(2):e139–42.Google Scholar
  38. 38.
    Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004;53(2):474–81.Google Scholar
  39. 39.
    Simon KC, Chen H, Schwarzschild M, Ascherio A. Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease. Neurology. 2007;69(17):1688–95.Google Scholar
  40. 40.
    Becker C, Brobert GP, Johansson S, Jick SS, Meier CR. Diabetes in patients with idiopathic Parkinson’s disease. Diabetes Care. 2008;31(9):1808–12.Google Scholar
  41. 41.
    Reaven GM. Insulin resistance in noninsulin-dependent diabetes mellitus. Does it exist and can it be measured? Am J Med. 1983;74(1A):3–17.Google Scholar
  42. 42.
    Greenhill C. Diabetes: new mechanism for insulin resistance. Nat Rev Endocrinol. 2016;12(5):249.Google Scholar
  43. 43.
    Mooradian AD. Central nervous system complications of diabetes mellitus—a perspective from the blood–brain barrier. Brain Res Brain Res Rev. 1997;23(3):210–8.Google Scholar
  44. 44.
    Acharya NK, Levin EC, Clifford PM, Han M, Tourtellotte R, Chamberlain D, et al. Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib. J Alzheimers Dis. 2013;35(1):179–98.Google Scholar
  45. 45.
    Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, et al. Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci. 2002;22(9):3359–65.Google Scholar
  46. 46.
    Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009;66(3):300–5.Google Scholar
  47. 47.
    Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65(4):545–51.Google Scholar
  48. 48.
    Haan MN, Wallace R. Can dementia be prevented? Brain aging in a population-based context. Annu Rev Public Health. 2004;25:1–24.Google Scholar
  49. 49.
    Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5(1):64–74.Google Scholar
  50. 50.
    Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280–92.Google Scholar
  51. 51.
    Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, et al. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci USA. 2000;97(11):6037–42.Google Scholar
  52. 52.
    Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med. 1996;334(12):752–8.Google Scholar
  53. 53.
    Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63–80.Google Scholar
  54. 54.
    Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31(2):224–43.Google Scholar
  55. 55.
    Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Investig. 2012;122(4):1316–38.Google Scholar
  56. 56.
    Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010;75(9):764–70.Google Scholar
  57. 57.
    Lee S, Tong M, Hang S, Deochand C, de la Monte S. CSF and brain indices of insulin resistance, oxidative stress and neuro-inflammation in early versus late Alzheimer’s disease. J Alzheimers Dis Parkinsonism. 2013;31(3):128.Google Scholar
  58. 58.
    Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, et al. Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA. 2003;100(18):10417–22.Google Scholar
  59. 59.
    Ferreira ST, Klein WL. The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem. 2011;96(4):529–43.Google Scholar
  60. 60.
    Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8(6):595–608.Google Scholar
  61. 61.
    Ferreira ST, Lourenco MV, Oliveira MM, De Felice FG. Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer’s disease. Front Cell Neurosci. 2015;9:191.Google Scholar
  62. 62.
    De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA. 2009;106(6):1971–6.Google Scholar
  63. 63.
    Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, et al. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008;22(1):246–60.Google Scholar
  64. 64.
    Qiao LY, Goldberg JL, Russell JC, Sun XJ. Identification of enhanced serine kinase activity in insulin resistance. J Biol Chem. 1999;274(15):10625–32.Google Scholar
  65. 65.
    Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, et al. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem. 1997;272(47):29911–8.Google Scholar
  66. 66.
    Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, et al. TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeys. Cell Metab. 2013;18(6):831–43.Google Scholar
  67. 67.
    Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Investig. 2012;122(4):1339–53.Google Scholar
  68. 68.
    Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009;29(28):9078–89.Google Scholar
  69. 69.
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271(5249):665–8.Google Scholar
  70. 70.
    Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415–45.Google Scholar
  71. 71.
    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405.Google Scholar
  72. 72.
    Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542(7640):177–85.Google Scholar
  73. 73.
    De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimers Dement. 2014;10(1 Suppl):S26–32.Google Scholar
  74. 74.
    Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013;22(2013):139239.Google Scholar
  75. 75.
    Piya MK, McTernan PG, Kumar S. Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin. J Endocrinol. 2013;216(1):T1–15.Google Scholar
  76. 76.
    Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A, et al. Raised interleukin-6 levels in obese patients. Obes Res. 2000;8(9):673–5.Google Scholar
  77. 77.
    Eder K, Baffy N, Falus A, Fulop AK. The major inflammatory mediator interleukin-6 and obesity. Inflamm Res. 2009;58(11):727–36.Google Scholar
  78. 78.
    Di Renzo L, Bigioni M, Del Gobbo V, Premrov MG, Barbini U, Di Lorenzo N, et al. Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: relationship to body composition and IL-1 alpha and beta plasma levels. Pharmacol Res. 2007;55(2):131–8.Google Scholar
  79. 79.
    Hoene M, Weigert C. The role of interleukin-6 in insulin resistance, body fat distribution and energy balance. Obes Rev. 2008;9(1):20–9.Google Scholar
  80. 80.
    Jager J, Gremeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148(1):241–51.Google Scholar
  81. 81.
    Rehman K, Akash MS. Mechanisms of inflammatory responses and development of insulin resistance: how are they interlinked? J Biomed Sci. 2016;23(1):87.Google Scholar
  82. 82.
    Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med. 2012;18(1):59–68.Google Scholar
  83. 83.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61.Google Scholar
  84. 84.
    Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry. 2010;68(10):930–41.Google Scholar
  85. 85.
    Brosseron F, Traschutz A, Widmann CN, Kummer MP, Tacik P, Santarelli F, et al. Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):25.Google Scholar
  86. 86.
    Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol. 2009;174(4):1241–51.Google Scholar
  87. 87.
    Ledo JH, Azevedo EP, Beckman D, Ribeiro FC, Santos LE, Razolli DS, et al. Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid-beta oligomers in mice. J Neurosci. 2016;36(48):12106–16.Google Scholar
  88. 88.
    Ledo JH, Azevedo EP, Clarke JR, Ribeiro FC, Figueiredo CP, Foguel D, et al. Amyloid-beta oligomers link depressive-like behavior and cognitive deficits in mice. Mol Psychiatry. 2013;18(10):1053–4.Google Scholar
  89. 89.
    Abisambra JF, Jinwal UK, Blair LJ, O’Leary JC 3rd, Li Q, Brady S, et al. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci. 2013;33(22):9498–507.Google Scholar
  90. 90.
    Scheper W, Hoozemans JJ. Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy. Curr Med Chem. 2009;16(5):615–26.Google Scholar
  91. 91.
    Shoji M, Iwakami N, Takeuchi S, Waragai M, Suzuki M, Kanazawa I, et al. JNK activation is associated with intracellular beta-amyloid accumulation. Brain Res Mol Brain Res. 2000;85(1–2):221–33.Google Scholar
  92. 92.
    Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.Google Scholar
  93. 93.
    Goldman JG, Williams-Gray C, Barker RA, Duda JE, Galvin JE. The spectrum of cognitive impairment in Lewy body diseases. Mov Disord. 2014;29(5):608–21.Google Scholar
  94. 94.
    Broeders M, Velseboer DC, de Bie R, Speelman JD, Muslimovic D, Post B, et al. Cognitive change in newly-diagnosed patients with Parkinson’s disease: a 5-year follow-up study. J Int Neuropsychol Soc. 2013;19(6):695–708.Google Scholar
  95. 95.
    Hoogland J, Boel JA, de Bie RMA, Geskus RB, Schmand BA, Dalrymple-Alford JC, et al. Mild cognitive impairment as a risk factor for Parkinson’s disease dementia. Mov Disord. 2017;32(7):1056–65.Google Scholar
  96. 96.
    Athauda D, Foltynie T. Protective effects of the GLP-1 mimetic exendin-4 in Parkinson’s disease. Neuropharmacology. 2017;Sep:18.Google Scholar
  97. 97.
    Pressley JC, Louis ED, Tang MX, Cote L, Cohen PD, Glied S, et al. The impact of comorbid disease and injuries on resource use and expenditures in parkinsonism. Neurology. 2003;60(1):87–93.Google Scholar
  98. 98.
    Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, et al. Diabetes and risk of Parkinson’s disease. Diabetes Care. 2011;34(4):910–5.Google Scholar
  99. 99.
    Chalmanov V, Vurbanova M. Diabetes mellitus in parkinsonism patients. Vutr Boles. 1987;26(1):68–73.Google Scholar
  100. 100.
    Schwab RS. Progression and prognosis in Parkinson’s disease. J Nerv Ment Dis. 1960;130:556–66.Google Scholar
  101. 101.
    Van Woert MH, Mueller PS. Glucose, insulin, and free fatty acid metabolism in Parkinson’s disease treated with levodopa. Clin Pharmacol Ther. 1971;12(2):360–7.Google Scholar
  102. 102.
    Sirtori CR, Bolme P, Azarnoff DL. Metabolic responses to acute and chronic L-dopa administration in patients with parkinsonism. N Engl J Med. 1972;287(15):729–33.Google Scholar
  103. 103.
    Van Woert MH, Mueller PS, Ambani LM, Rathey U. Abnormal insulin secretion in Parkinson’s disease before and during L-dihydroxyphenylalanine (L-dopa) therapy. J Endocrinol. 1973;59(3):523–34.Google Scholar
  104. 104.
    Levy G, Tang MX, Cote LJ, Louis ED, Alfaro B, Mejia H, et al. Do risk factors for Alzheimer’s disease predict dementia in Parkinson’s disease? An exploratory study. Mov Disord. 2002;17(2):250–7.Google Scholar
  105. 105.
    Liepelt I, Reimold M, Maetzler W, Godau J, Reischl G, Gaenslen A, et al. Cortical hypometabolism assessed by a metabolic ratio in Parkinson’s disease primarily reflects cognitive deterioration-[18F]FDG-PET. Mov Disord. 2009;24(10):1504–11.Google Scholar
  106. 106.
    Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley KE, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging. 2014;35(5):1111–5.Google Scholar
  107. 107.
    Unger JW, Moss AM, Livingston JN. Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience. 1991;42(3):853–61.Google Scholar
  108. 108.
    Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer EG, et al. Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson’s disease. Acta Neuropathol. 1994;87(4):343–8.Google Scholar
  109. 109.
    Liu S, Labouebe G, Karunakaran S, Clee SM, Borgland SL. Effect of insulin on excitatory synaptic transmission onto dopamine neurons of the ventral tegmental area in a mouse model of hyperinsulinemia. Nutr Diabetes. 2013;16(3):e97.Google Scholar
  110. 110.
    Godau J, Knauel K, Weber K, Brockmann K, Maetzler W, Binder G, et al. Serum insulinlike growth factor 1 as possible marker for risk and early diagnosis of Parkinson disease. Arch Neurol. 2011;68(7):925–31.Google Scholar
  111. 111.
    Ma J, Jiang Q, Xu J, Sun Q, Qiao Y, Chen W, et al. Plasma insulin-like growth factor 1 is associated with cognitive impairment in Parkinson’s disease. Dement Geriatr Cogn Disord. 2015;39(5–6):251–6.Google Scholar
  112. 112.
    Mashayekhi F, Mirzajani E, Naji M, Azari M. Expression of insulin-like growth factor-1 and insulin-like growth factor binding proteins in the serum and cerebrospinal fluid of patients with Parkinson’s disease. J Clin Neurosci. 2010;17(5):623–7.Google Scholar
  113. 113.
    Morris JK, Bomhoff GL, Gorres BK, Davis VA, Kim J, Lee PP, et al. Insulin resistance impairs nigrostriatal dopamine function. Exp Neurol. 2011;231(1):171–80.Google Scholar
  114. 114.
    Morris JK, Bomhoff GL, Stanford JA, Geiger PC. Neurodegeneration in an animal model of Parkinson’s disease is exacerbated by a high-fat diet. Am J Physiol Regul Integr Comp Physiol. 2010;299(4):R1082–90.Google Scholar
  115. 115.
    Torres-Aleman I. Toward a comprehensive neurobiology of IGF-I. Dev Neurobiol. 2010;70(5):384–96.Google Scholar
  116. 116.
    Skow MA, Bergmann NC, Knop FK. Diabetes and obesity treatment based on dual incretin receptor activation: ‘twincretins’. Diabetes Obes Metab. 2016;18(9):847–54.Google Scholar
  117. 117.
    Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203–16.Google Scholar
  118. 118.
    Varndell IM, Bishop AE, Sikri KL, Uttenthal LO, Bloom SR, Polak JM. Localization of glucagon-like peptide (GLP) immunoreactants in human gut and pancreas using light and electron microscopic immunocytochemistry. J Histochem Cytochem. 1985;33(10):1080–6.Google Scholar
  119. 119.
    Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44(9):1126–31.Google Scholar
  120. 120.
    Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80(3):952–7.Google Scholar
  121. 121.
    Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–39.Google Scholar
  122. 122.
    Kjems LL, Holst JJ, Volund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003;52(2):380–6.Google Scholar
  123. 123.
    Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience. 1997;77(1):257–70.Google Scholar
  124. 124.
    Llewellyn-Smith IJ, Reimann F, Gribble FM, Trapp S. Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience. 2011;28(180):111–21.Google Scholar
  125. 125.
    Merchenthaler I, Lane M, Shughrue P. Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol. 1999;403(2):261–80.Google Scholar
  126. 126.
    Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718–31.Google Scholar
  127. 127.
    Heppner KM, Kirigiti M, Secher A, Paulsen SJ, Buckingham R, Pyke C, et al. Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology. 2015;156(1):255–67.Google Scholar
  128. 128.
    Farr OM, Sofopoulos M, Tsoukas MA, Dincer F, Thakkar B, Sahin-Efe A, et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia. 2016;59(5):954–65.Google Scholar
  129. 129.
    Llewellyn-Smith IJ, Gnanamanickam GJ, Reimann F, Gribble FM, Trapp S. Preproglucagon (PPG) neurons innervate neurochemically identified autonomic neurons in the mouse brainstem. Neuroscience. 2013;15(229):130–43.Google Scholar
  130. 130.
    Vrang N, Hansen M, Larsen PJ, Tang-Christensen M. Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. Brain Res. 2007;29(1149):118–26.Google Scholar
  131. 131.
    During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9(9):1173–9.Google Scholar
  132. 132.
    Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer’s disease. Behav Brain Res. 2009;205(1):265–71.Google Scholar
  133. 133.
    Mattson MP, Perry T, Greig NH. Learning from the gut. Nat Med. 2003;9(9):1113–5.Google Scholar
  134. 134.
    Ritzel U, Leonhardt U, Ottleben M, Ruhmann A, Eckart K, Spiess J, et al. A synthetic glucagon-like peptide-1 analog with improved plasma stability. J Endocrinol. 1998;159(1):93–102.Google Scholar
  135. 135.
    Werner U, Haschke G, Herling AW, Kramer W. Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept. 2010;164(2–3):58–64.Google Scholar
  136. 136.
    Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A. Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Ther. 2015;6(3):239–56.Google Scholar
  137. 137.
    Andersen A, Lund A, Knop FK, Vilsboll T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol. 2018;14(7):390–403.Google Scholar
  138. 138.
    Christensen M, Sparre-Ulrich AH, Hartmann B, Grevstad U, Rosenkilde MM, Holst JJ, et al. Transfer of liraglutide from blood to cerebrospinal fluid is minimal in patients with type 2 diabetes. Int J Obes (Lond). 2015;39(11):1651–4.Google Scholar
  139. 139.
    Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;23(13):33.Google Scholar
  140. 140.
    Kastin AJ, Akerstrom V. Entry of exendin-4 into brain is rapid but may be limited at high doses. Int J Obes Relat Metab Disord. 2003;27(3):313–8.Google Scholar
  141. 141.
    Bhavsar S, Mudaliar S, Cherrington A. Evolution of exenatide as a diabetes therapeutic. Curr Diabetes Rev. 2013;9(2):161–93.Google Scholar
  142. 142.
    Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003;72(5):603–12.Google Scholar
  143. 143.
    Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW, et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer’s disease. J Alzheimers Dis. 2010;19(4):1205–19.Google Scholar
  144. 144.
    McClean PL, Holscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology. 2014;76(Pt A):57–67.Google Scholar
  145. 145.
    McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci. 2011;31(17):6587–94.Google Scholar
  146. 146.
    Liu XY, Wang LX, Chen Z, Liu LB. Liraglutide prevents beta-amyloid-induced neurotoxicity in SH-SY5Y cells via a PI3K-dependent signaling pathway. Neurol Res. 2016;38(4):313–9.Google Scholar
  147. 147.
    Sharma MK, Jalewa J, Holscher C. Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress. J Neurochem. 2014;128(3):459–71.Google Scholar
  148. 148.
    Qi L, Chen Z, Wang Y, Liu X, Liu X, Ke L, et al. Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3beta. Am J Transl Res. 2017;9(2):247–60.Google Scholar
  149. 149.
    Qi L, Ke L, Liu X, Liao L, Ke S, Liu X, et al. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced alzheimer disease mouse model. Eur J Pharmacol. 2016;15(783):23–32.Google Scholar
  150. 150.
    Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, et al. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;46(4):877–88.Google Scholar
  151. 151.
    Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S, et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis. 2013;37(3):637–48.Google Scholar
  152. 152.
    Chen S, Sun J, Zhao G, Guo A, Chen Y, Fu R, et al. Liraglutide improves water maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/tau triple transgenic mice. Neurochem Res. 2017;42(8):2326–35.Google Scholar
  153. 153.
    McClean PL, Jalewa J, Holscher C. Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res. 2015;15(293):96–106.Google Scholar
  154. 154.
    Hansen HH, Fabricius K, Barkholt P, Kongsbak-Wismann P, Schlumberger C, Jelsing J, et al. Long-term treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has no effect on beta-amyloid plaque load in two transgenic APP/PS1 mouse models of Alzheimer’s disease. PLoS One. 2016;11(7):e0158205.Google Scholar
  155. 155.
    Batista AF, Forny-Germano L, Clarke JR, Lyra ESNM, Brito-Moreira J, Boehnke SE, et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J Pathol. 2018;245(1):85–100.Google Scholar
  156. 156.
    McClean PL, Holscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology. 2014;86:241–58.Google Scholar
  157. 157.
    Cai HY, Yang JT, Wang ZJ, Zhang J, Yang W, Wu MN, et al. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer’s disease. Biochem Biophys Res Commun. 2018;495(1):1034–40.Google Scholar
  158. 158.
    Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA. 2009;106(4):1285–90.Google Scholar
  159. 159.
    Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J Endocrinol. 2009;202(3):431–9.Google Scholar
  160. 160.
    Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflamm. 2008;21(5):19.Google Scholar
  161. 161.
    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(2):326–38.Google Scholar
  162. 162.
    Liu W, Jalewa J, Sharma M, Li G, Li L, Holscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience. 2015;10(303):42–50.Google Scholar
  163. 163.
    Zhang L, Zhang L, Li L, Holscher C. Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson’s disease mouse model. Neuropeptides. 2018;71:70–80.Google Scholar
  164. 164.
    Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;24(7):931–8.Google Scholar
  165. 165.
    McManus RM, Heneka MT. Role of neuroinflammation in neurodegeneration: new insights. Alzheimers Res Ther. 2017;9(1):14.Google Scholar
  166. 166.
    McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988;38(8):1285–91.Google Scholar
  167. 167.
    Duke DC, Moran LB, Pearce RK, Graeber MB. The medial and lateral substantia nigra in Parkinson’s disease: mRNA profiles associated with higher brain tissue vulnerability. Neurogenetics. 2007;8(2):83–94.Google Scholar
  168. 168.
    Sekiyama K, Sugama S, Fujita M, Sekigawa A, Takamatsu Y, Waragai M, et al. Neuroinflammation in Parkinson’s disease and related disorders: a lesson from genetically manipulated mouse models of alpha-synucleinopathies. Parkinsons Dis. 2012;2012:271732.Google Scholar
  169. 169.
    Brodacki B, Staszewski J, Toczylowska B, Kozlowska E, Drela N, Chalimoniuk M, et al. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008;441(2):158–62.Google Scholar
  170. 170.
    Reale M, Greig NH, Kamal MA. Peripheral chemo-cytokine profiles in Alzheimer’s and Parkinson’s diseases. Mini Rev Med Chem. 2009;9(10):1229–41.Google Scholar
  171. 171.
    Song IU, Kim JS, Chung SW, Lee KS. Is there an association between the level of high-sensitivity C-reactive protein and idiopathic Parkinson’s disease? A comparison of Parkinson’s disease patients, disease controls and healthy individuals. Eur Neurol. 2009;62(2):99–104.Google Scholar
  172. 172.
    Brosseron F, Krauthausen M, Kummer M, Heneka MT. Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol Neurobiol. 2014;50(2):534–44.Google Scholar
  173. 173.
    Motta M, Imbesi R, Di Rosa M, Stivala F, Malaguarnera L. Altered plasma cytokine levels in Alzheimer’s disease: correlation with the disease progression. Immunol Lett. 2007;114(1):46–51.Google Scholar
  174. 174.
    Forloni G, Balducci C. Alzheimer’s disease, oligomers, and inflammation. J Alzheimers Dis. 2018;62(3):1261–76.Google Scholar
  175. 175.
    Tai J, Liu W, Li Y, Li L, Holscher C. Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Brain Res. 2018;1(1678):64–74.Google Scholar
  176. 176.
    Feng P, Zhang X, Li D, Ji C, Yuan Z, Wang R, et al. Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson’s disease. Neuropharmacology. 2018;1(133):385–94.Google Scholar
  177. 177.
    Yuan Z, Li D, Feng P, Xue G, Ji C, Li G, et al. A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson’s disease. Eur J Pharmacol. 2017;5(812):82–90.Google Scholar
  178. 178.
    Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957–67.Google Scholar
  179. 179.
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.Google Scholar
  180. 180.
    Li Y, Liu W, Li L, Holscher C. D-Ala2-GIP-glu-PAL is neuroprotective in a chronic Parkinson’s disease mouse model and increases BNDF expression while reducing neuroinflammation and lipid peroxidation. Eur J Pharmacol. 2017;15(797):162–72.Google Scholar
  181. 181.
    Li Y, Liu W, Li L, Holscher C. Neuroprotective effects of a GIP analogue in the MPTP Parkinson’s disease mouse model. Neuropharmacology. 2016;101:255–63.Google Scholar
  182. 182.
    Duffy AM, Holscher C. The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer’s disease. Neuroscience. 2013;3(228):294–300.Google Scholar
  183. 183.
    Faivre E, Holscher C. D-Ala2GIP facilitated synaptic plasticity and reduces plaque load in aged wild type mice and in an Alzheimer’s disease mouse model. J Alzheimers Dis. 2013;35(2):267–83.Google Scholar
  184. 184.
    Faivre E, Hamilton A, Holscher C. Effects of acute and chronic administration of GIP analogues on cognition, synaptic plasticity and neurogenesis in mice. Eur J Pharmacol. 2012;674(2–3):294–306.Google Scholar
  185. 185.
    Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6):819–37.Google Scholar
  186. 186.
    Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885–909.Google Scholar
  187. 187.
    Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95(2):513–48.Google Scholar
  188. 188.
    Finan B, Ma T, Ottaway N, Muller TD, Habegger KM, Heppner KM, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5(209):209ra151.Google Scholar
  189. 189.
    Frias JP, Bastyr EJ 3rd, Vignati L, Tschop MH, Schmitt C, Owen K, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 2017;26(2):343–52.Google Scholar
  190. 190.
    Zhou J, Cai X, Huang X, Dai Y, Sun L, Zhang B, et al. A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects. Eur J Med Chem. 2017;29(138):1158–69.Google Scholar
  191. 191.
    Jall S, Sachs S, Clemmensen C, Finan B, Neff F, DiMarchi RD, et al. Monomeric GLP-1/GIP/glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice. Mol Metab. 2017;6(5):440–6.Google Scholar
  192. 192.
    Jalewa J, Sharma MK, Gengler S, Holscher C. A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson’s disease. Neuropharmacology. 2017;1(117):238–48.Google Scholar
  193. 193.
    Cao Y, Holscher C, Hu MM, Wang T, Zhao F, Bai Y, et al. DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer’s disease. Eur J Pharmacol. 2018;15(827):215–26.Google Scholar
  194. 194.
    Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Investig. 2013;123(6):2730–6.Google Scholar
  195. 195.
    Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Kahan J, Ell P, et al. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4(3):337–44.Google Scholar
  196. 196.
    Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664–75.Google Scholar
  197. 197.
    Mansur RB, Ahmed J, Cha DS, Woldeyohannes HO, Subramaniapillai M, Lovshin J, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord. 2017;1(207):114–20.Google Scholar
  198. 198.
    Egefjord L, Gejl M, Moller A, Braendgaard H, Gottrup H, Antropova O, et al. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease—protocol for a controlled, randomized double-blinded trial. Dan Med J. 2012;59(10):A4519.Google Scholar
  199. 199.
    Gejl M, Gjedde A, Egefjord L, Moller A, Hansen SB, Vang K, et al. In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci. 2016;8:108.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Institute of Biomedical Sciences, Federal University of Rio de JaneiroRio de JaneiroBrazil
  3. 3.Department of Psychiatry, Centre for Neuroscience StudiesQueen’s UniversityKingstonCanada
  4. 4.Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de JaneiroRio de JaneiroBrazil

Personalised recommendations