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

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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.

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About the authors

Elena V Surkova

Endocrinology Research Centre

SPIN-code: 7944-3869
MD, PhD 11, Dm. Ulyanova street, Moscow, 117036

Kira V Derkach

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

SPIN-code: 6925-1558
PhD 44, Thorez prospekt, St.-Petersburg, 194223

Alexey I Bespalov

Endocrinology Research Centre

SPIN-code: 9466-2528
MD 11, Dm. Ulyanova street, Moscow, 117036

Alexander O Shpakov

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

SPIN-code: 6335-8311
PhD 44, Thorez prospekt, St.-Petersburg, 194223


  1. Roger LJ, Fellows RE. Stimulation of ornithine decarboxylase activity by insulin in developing rat brain. Endocrinology. 1980;106(2):619-625. doi:
  2. De La Monte SM. Insulin resistance and Alzheimer’s disease. Bmb Rep. 2009;42(8):475-481. doi:
  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:<1044:: aid-dia508>;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:
  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:
  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:
  8. Hirai S, Ikenaga T, Matsuzawa T. Nasal absorption of insulin in dogs. Diabetes. 1978;27(3):296-299. doi:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  20. Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron. 2011;69(4):664-679. doi:
  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:
  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:
  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:
  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:
  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:
  27. Störtebecker P. Mercury poisoning from dental amalgam through a direct nose-brain transport. Lancet. 1989;333(8648):1207. doi:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  40. Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10): 1326-1334. doi:
  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:
  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:
  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:
  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:
  45. Craft S, Stennis Watson G. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol. 2004;3(3):169-178. doi:
  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:
  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:
  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:
  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:
  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:
  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:
  52. Brange J, Vølund A. Insulin analogs with improved pharmacokinetic profiles. Adv Drug Deliv Rev. 1999;35(2-3):307-335. doi:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  62. Jensen MD, Nielsen S, Gupta N, et al. Insulin clearance is different in men and women. Metabolism. 2012;61(4):525-530. doi:
  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:
  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:
  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:
  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:
  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:
  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:
  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:
  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:

Copyright (c) 2020 Surkova E.V., Derkach K.V., Bespalov A.I., Shpakov A.O.

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