Уважаемые пользователи!

Данный сайт содержит информацию для людей с медицинским образованием и специалистов здравоохранения.
Входя на сайт, Вы подтверждаете свое согласие с Условиями использования и Политикой конфиденциальности.



Dear visitor!
This site contains medical information for healthcare professionals.
You can go further, if you agree with Terms and Conditions and Privacy Policy on this site.

Prospects of intranasal insulin for correction of cognitive impairments, in particular those associated with diabetes mellitus

Cover Page
Open Access Open Access
Restricted Access Subscription Access

Abstract


Despite the well-studied effect of insulin in peripheral tissues, its role in functioning of the central nervous system is much less understood. The effects of insulin in the brain are extremely diverse: insulin plays an important role in neuron growth and differentiation, affects higher cognitive functions (in particular, the formation of long-term memory), and also has a neuroprotective effect. Both peripheral and central insulin resistance as well as absolute insulin deficiency impairs the functional activity of neurons and neurogenesis. Several studies have investigated intranasal administration of insulin as a potential way for correction of these disorders. The review presents data on abnormalities of the insulin signaling system in the brain in diabetes mellitus, which is accompanied by cognitive dysfunction of varying severity and is associated with the development of neurodegenerative disorders, including Alzheimer’s disease. We analyzed the results of studies on the use of intranasal insulin in animal models with diabetes mellitus, healthy volunteers, and patients with cognitive impairments.


Elena V. Surkova

Endocrinology Research Centre

Email: elenasurkova@mail.ru
ORCID iD: 0000-0002-3973-7638
SPIN-code: 7944-3869
https://www.endocrincentr.ru/doctors/surkova-elena-viktorovna

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD

Kira V. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences

Email: derkatch_kira@list.ru
ORCID iD: 0000-0001-6555-9540
SPIN-code: 6925-1558

Russian Federation, 44, Thorez prospekt, St.-Petersburg, 194223

PhD

Alexey I. Bespalov

Endocrinology Research Centre

Author for correspondence.
Email: finger1ess@mail.ru
ORCID iD: 0000-0003-1584-5690
SPIN-code: 9466-2528

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD

Alexander O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences

Email: alex_shpakov@list.ru
ORCID iD: 0000-0002-4293-3162
SPIN-code: 6335-8311

Russian Federation, 44, Thorez prospekt, St.-Petersburg, 194223

PhD

  1. Roger LJ, Fellows RE. Stimulation of ornithine decarboxylase activity by insulin in developing rat brain. Endocrinology. 1980;106(2):619-625. doi: https://doi.org/10.1210/endo-106-2-619
  2. De La Monte SM. Insulin resistance and Alzheimer’s disease. Bmb Rep. 2009;42(8):475-481. doi: https://doi.org/10.5483/bmbrep.2009.42.8.475
  3. Hopkins DFC, Williams G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med. 1997;14(12):1044-1050. doi: https://doi.org/10.1002/(sici)1096-9136(199712)14:12<1044:: aid-dia508>3.0.co;2-f
  4. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res. 2012;2012:384017. doi: https://doi.org/10.1155/2012/384017
  5. Sergeant N, Delacourte A, Buee L. Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta. 2005;1739(2-3):179-197. doi: https://doi.org/10.1016/j.bbadis.2004.06.020
  6. Шпаков А.О., Деркач К.В. Гормональные системы мозга и сахарный диабет 2-го типа. — СПб.: Издательство Политехнического университета, 2015. [Shpakov AO, Derkach KV. Gormonal’nye Sistemy Mozga I Sakharnyy Diabet 2-Go Tipa. Saint-Petersburg: Izdatel’stvo Politekhnicheskogo Universiteta; 2015. (In Russ.)].
  7. Gizurarson S, Bechgaard E. Intranasal administration of insulin to humans. Diabetes Res Clin Pract. 1991;12(2):71-84. doi: https://doi.org/10.1016/0168-8227(91)90083-p
  8. Hirai S, Ikenaga T, Matsuzawa T. Nasal absorption of insulin in dogs. Diabetes. 1978;27(3):296-299. doi: https://doi.org/10.2337/diab.27.3.296
  9. Frauman AG, Jerums G, Louis WJ. Effects of intranasal insulin in non-obese type II diabetics. Diabetes Res Clin Pract. 1987;3(4):197-202. doi: https://doi.org/10.1016/s0168-8227(87)80039-6
  10. Moses AC, Flier JS, Gordon GS, et al. Transnasal insulin delivery-structure-function studies of absorption enhancing adjuvants. Clin Res. 1984;32(2):A245.
  11. Drejer K, Vaag A, Bech K, et al. Pharmacokinetics of intranasally administered insulin with phospholipids as absorption enhancers. Diabetologia. 1990;53(Suppl 1):A61.
  12. Silver RD, Moses AC, Carey MC, Flier JS. Insulin-bile salt nasal aerosol markedly reduces postprandial glycemic excursion in diabetics. Diabetes. 1984;33(Suppl 1):75a.
  13. Pontiroli AE, Alberetto M, Pajetta E, et al. Human insulin plus sodium glycocholate in a nasal spray formulation: improved bioavailability and effectiveness in normal subjects. Diabetes Metab. 1987;13(4):441-443.
  14. Havrankova J, Brownstein M, Roth J. Insulin and insulin receptors in rodent brain. Diabetologia. 1981;20(suppl 1):268-273. doi: https://doi.org/10.1007/bf00254492
  15. Chen M, Woods SC, Porte D. Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog. Diabetes. 1975;24(10):910-914. doi: https://doi.org/10.2337/diab.24.10.910
  16. Chowers I, Lavy S, Halpern L. Effect of insulin administered intracisternally on the glucose level of the blood and the cerebrospinal fluid in vagotomized dogs. Exp Neurol. 1966;14(3):383-389. doi: https://doi.org/10.1016/0014-4886(66)90122-1
  17. Figlewicz DP. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am j physiol regul integr comp physiol. 2003;284(4):r882-r892. doi: https://doi.org/10.1152/ajpregu.00602.2002
  18. Porte D, Baskin DG, Schwartz MW. Leptin and insulin action in the central nervous system. Nutr Rev. 2002;60(suppl_10):s20-s29. doi: https://doi.org/10.1301/002966402320634797
  19. Brief DJ, Davis JD. Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res Bull. 1984; 12(5):571-575. doi: https://doi.org/10.1016/0361-9230(84)90174-6
  20. Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron. 2011;69(4):664-679. doi: https://doi.org/10.1016/j.neuron.2011.02.016
  21. Volkow ND, Wang GJ, Baler RD. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci. 2011;15(1):37-46. doi: https://doi.org/10.1016/j.tics.2010.11.001
  22. Craft S, Asthana S, Newcomer JW, et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry. 1999;56(12):1135. doi: https://doi.org/10.1001/archpsyc.56.12.1135
  23. Craft S, Newcomer J, Kanne S, et al. Memory improvement following induced hyperinsulinemia in Alzheimer’s disease. Neurobiol Aging. 1996;17(1):123-130. doi: https://doi.org/10.1016/0197-4580(95)02002-0
  24. Evans J, Hastings L. Accumulation of CD(II) in the CNS depending on the route of administration: intraperitoneal, intratracheal, or intranasal. Toxicol Sci. 1992;19(2):275-278. doi: https://doi.org/10.1093/toxsci/19.2.275
  25. Hastings L, Evans JE. Olfactory primary neurons as a route of entry for toxic agents into the CNS. Neurotoxicology. 1991;12(4):707-714.
  26. Perl D, Good P. Uptake of aluminium into central nervous system along nasal-olfactory pathways. Lancet. 1987;329(8540):1028. doi: https://doi.org/10.1016/s0140-6736(87)92288-4
  27. Störtebecker P. Mercury poisoning from dental amalgam through a direct nose-brain transport. Lancet. 1989;333(8648):1207. doi: https://doi.org/10.1016/s0140-6736(89)92789-x
  28. Sakane T, Akizuki M, Yoshida M, et al. Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity. J Pharm Pharmacol. 1991;43(6):449-451. doi: https://doi.org/10.1111/j.2042-7158.1991.tb03510.x
  29. Balin BJ, Broadwell RD, Salcman M, El-Kalliny M. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol. 1986;251(2):260-280. doi: https://doi.org/10.1002/cne.902510209
  30. Baker H, Spencer RF. Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat. Exp Brain Res. 1986;63(3):461-473. doi: https://doi.org/10.1007/bf00237470
  31. Pietrowsky R, Born J, Kern W, Fehm HL. Functional evidence for a transmission of peptides along the olfactory systems into the brain in healthy humans. In: Krisch B, Mentlein R, editors. The peptidergic neuron. Advances in life sciences. Basel: Birkhäuser Basel, 1996. doi: https://doi.org/10.1007/978-3-0348-9010-6_32
  32. Kern W, Born J, Schreiber H, Fehm HL. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999;48(3):557-563. doi: https://doi.org/10.2337/diabetes.48.3.557
  33. Kupila A, Sipila J, Keskinen P, et al. Intranasally administered insulin intended for prevention of type 1 diabetes— a safety study in healthy adults. Diabetes Metab Res Rev. 2003;19(5):415-420. doi: https://doi.org/10.1002/dmrr.397
  34. Kopf SR, Baratti CM. Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem. 1999;71(1):50-61. doi: https://doi.org/10.1006/nlme.1998.3831
  35. Kopf SR, Boccia MM, Baratti CM. AF-DX 116, a presynaptic muscarinic receptor antagonist, potentiates the effects of glucose and reverses the effects of insulin on memory. Neurobiol Learn Mem. 1998;70(3):305-313. doi: https://doi.org/10.1006/nlme.1998.3855
  36. Park C, Seeley R, Craft S, Woods S. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav. 2000;68(4):509-514. doi: https://doi.org/10.1016/s0031-9384(99)00220-6
  37. Kern W, Peters A, Fruehwald-Schultes B, et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74(4):270-280. doi: https://doi.org/10.1159/000054694
  38. Unger J, Livingston J, Moss A. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol. 1991;36(5):343-362. doi: https://doi.org/10.1016/0301-0082(91)90015-s
  39. Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci. 1998;112(5):1199-1208. doi: https://doi.org/10.1037/0735-7044.112.5.1199
  40. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10): 1326-1334. doi: https://doi.org/10.1016/j.psyneuen.2004.04.003
  41. Hallschmid M, Benedict C, Schultes B, et al. Intranasal insulin reduces body fat in men but not in women. Diabetes. 2004;53(11): 3024-3029. doi: https://doi.org/10.2337/diabetes.53.11.3024
  42. Clegg DJ, Riedy CA, Smith KAB, et al. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52(3):682-687. doi: https://doi.org/10.2337/diabetes.52.3.682
  43. Clegg DJ, Bbrown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes. 2006;55(4):978-987. doi: https://doi.org/10.2337/diabetes.55.04.06.db05-1339
  44. Craft S, Peskind E, Schwartz MW, et al. Cerebrospinal fluid and plasma insulin levels in alzheimer’s disease: relationship to severity of dementia and apolipoprotein e genotype. Neurology. 1998; 50(1):164-168. doi: https://doi.org/10.1212/wnl.50.1.164
  45. Craft S, Stennis Watson G. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3(3):169-178. doi: https://doi.org/10.1016/s1474-4422(04)00681-7
  46. Frolich L, Blum-Degen D, Bernstein HG, et al. Brain insulin and insulin receptors in aging and sporadic alzheimer’s disease. J Neural Transm (Vienna). 1998;105(4-5):423-438. doi: https://doi.org/10.1007/s007020050068
  47. Schwartz MW, Figlewicz DF, Kahn SE, et al. Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic zucker rats. Peptides. 1990;11(3):467-472. doi: https://doi.org/10.1016/0196-9781(90)90044-6
  48. Craft S, Asthana S, Schellenberg G, et al. Insulin metabolism in alzheimer’s disease differs according to apolipoprotein e genotype and gender. Neuroendocrinology. 1999;70(2):146-152. doi: https://doi.org/10.1159/000054469
  49. Craft S, Asthana S, Schellenberg G, et al. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer’s disease differ according to apolipoprotein E genotype. Ann NY Acad Sci. 2000;903(1 vascular fact):222-228. doi: https://doi.org/10.1111/j.1749-6632.2000.tb06371.x
  50. Benedict C, Hallschmid M, Schmitz K, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32(1):239-243. doi: https://doi.org/10.1038/sj.npp.1301193
  51. Kang S, Creagh FM, Peters JR, et al. Comparison of subcutaneous soluble human insulin and insulin analogues (aspb9, glub27; aspb10; aspb28) on meal-related plasma glucose excursions in type i diabetic subjects. Diabetes Care. 1991;14(7):571-577. doi: https://doi.org/10.2337/diacare.14.7.571
  52. Brange J, Vølund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 1999;35(2-3):307-335. doi: https://doi.org/10.1016/s0169-409x(98)00079-9
  53. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-β in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323-331. doi: https://doi.org/10.3233/jad-2008-13309
  54. Craft S, Asthana S, Cook DG, et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein e genotype. Psychoneuroendocrinology. 2003;28(6):809-822. doi: https://doi.org/10.1016/s0306-4530(02)00087-2
  55. Akomolafe A, Beiser A, Meigs JB, et al. Diabetes mellitus and risk of developing alzheimer disease: results from the framingham study. Arch Neurol. 2006;63(11):1551-1555. doi: https://doi.org/10.1001/archneur.63.11.1551
  56. Kuusisto J, Koivisto K, Mykkanen L, et al. Association between features of the insulin resistance syndrome and Alzheimer’s disease independently of apolipoprotein e4 phenotype: cross sectional population based study. BMJ. 1997;315(7115):1045-1049. doi: https://doi.org/10.1136/bmj.315.7115.1045
  57. Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708-719. doi: https://doi.org/10.1016/j.neuron.2008.04.014
  58. De felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of a beta oligomers. Proc Natl Acad Sci USA. 2009;106(6):1971-1976. doi: https://doi.org/10.1073/pnas.0809158106
  59. Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol aging. 2009;30(3):377-387. doi: https://doi.org/10.1016/j.neurobiolaging.2007.06.014
  60. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch neurol. 2012;69(1):29-38. doi: https://doi.org/10.1001/archneurol.2011.233
  61. Claxton A, Baker LD, Wilkinson CW, et al. Sex and APOE genotype differences in treatment response to two doses of intranasal insulin in adults with mild cognitive impairment or Alzheimer’s disease. J Alzheimers Dis. 2013;35(4):789-797. doi: https://doi.org/10.3233/jad-122308
  62. Jensen MD, Nielsen S, Gupta N, et al. Insulin clearance is different in men and women. Metabolism. 2012;61(4):525-530. doi: https://doi.org/10.1016/j.metabol.2011.08.009
  63. Vistisen D, Witte DR, Tabak AG, et al. Sex differences in glucose and insulin trajectories prior to diabetes diagnosis: the whitehall II study. Acta Diabetol. 2014;51(2):315-319. doi: https://doi.org/10.1007/s00592-012-0429-7
  64. Cholerton B, Baker LD, Trittschuh EH, et al. Insulin and sex interactions in older adults with mild cognitive impairment. J Alzheimers Dis. 2012;31(2):401-410. doi: https://doi.org/10.3233/jad-2012-120202
  65. Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37(3):751-759. doi: https://doi.org/10.2337/dc13-1672
  66. Zhang H, Hao Y, Manor B, et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes. 2015;64(3):1025-1034. doi: https://doi.org/10.2337/db14-1000
  67. Селиверстова Е.В., Селиверстов Ю.А., Коновалов Р.Н., Иллариошкин С.Н. Функциональная магнитно-резонансная томография покоя: новые возможности изучения физиологии и патологии мозга. // Анналы клинической и экспериментальной неврологии. — 2013. — Т. 7. — №4. — С. 39-44. [Seliverstova EV, Seliverstov YuA, Konovalov RN, Illarioshkin SN. Resting-state FMRIi: new possibilities for studying physiology and pathology of the brain. Annaly Klinicheskoy i Eksperimental’noy Nevrologii. 2013;7(4):39-44. (In Russ.)].
  68. Musen G, Jacobson AM, Bolo NR, et al. Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes. 2012;61(9): 2375-2379. doi: https://doi.org/10.2337/db11-1669
  69. Chen YC, Jiao Y, Cui Y, et al. Aberrant brain functional connectivity related to insulin resistance in type 2 diabetes: a resting-state fmri study. Diabetes care. 2014;37(6):1689-1696. doi: https://doi.org/10.2337/dc13-2127
  70. Hoogenboom WS, Marder TJ, Flores VL, et al. Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes. Diabetes. 2014;63(2):728-738. doi: https://doi.org/10.2337/db13-1219
  71. Чистякова О.В., Бондарева В.М., Шипилов В.Н., и др. Интраназальное введение инсулина устраняет дефицит долговременной пространственной памяти у крыс с неонатальным сахарным диабетом. // Доклады Академии наук. — 2011. — Т. 440. — №2. — С. 275-278. [Chistyakova OV, Bondareva VM, Shipilov VN, et al. Intranasal administration of insulin eliminates the deficit of long-term spatial memory in rats with neonatal diabetes mellitus. Dokl Akad Nauk. 2011;440(2):275-278. (In Russ.)].
  72. Chistyakova OV, Bondareva VM, Shipilov VN, et al. A positive effect of intranasal insulin on spatial memory in rats with neonatal diabetes mellitus. Endocrinology studies. 2011;1(2):16. doi: https://doi.org/10.4081/es.2011.e16

Supplementary files

There are no supplementary files to display.

Views

Abstract - 183

PDF (Russian) - 2

PlumX


Copyright (c) 2019 Surkova E.V., Derkach K.V., Bespalov A.I., Shpakov A.O.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.