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Insulin in the Brain: Sources, Localization and Functions

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Abstract

Historically, insulin is best known for its role in peripheral glucose homeostasis, and insulin signaling in the brain has received less attention. Insulin-independent brain glucose uptake has been the main reason for considering the brain as an insulin-insensitive organ. However, recent findings showing a high concentration of insulin in brain extracts, and expression of insulin receptors (IRs) in central nervous system tissues have gathered considerable attention over the sources, localization, and functions of insulin in the brain. This review summarizes the current status of knowledge of the peripheral and central sources of insulin in the brain, site-specific expression of IRs, and also neurophysiological functions of insulin including the regulation of food intake, weight control, reproduction, and cognition and memory formation. This review also considers the neuromodulatory and neurotrophic effects of insulin, resulting in proliferation, differentiation, and neurite outgrowth, introducing insulin as an attractive tool for neuroprotection against apoptosis, oxidative stress, beta amyloid toxicity, and brain ischemia.

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References

  1. Eknoyan G, Nagy J (2005) A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease. Adv Chronic Kidney Dis 12(2):223–229

    Article  PubMed  Google Scholar 

  2. Skljarevski V (2007) Historical aspects of diabetic neuropathies. Diabet Neuropathy 2007:1–5. doi:10.1007/978-1-59745-311-0_1

    Article  Google Scholar 

  3. Strakosch C, The discovery of insulin. University Endocrine Department Greenslopes Private Hospital, Brisbane, Australia. Available at http://www.historicgreenslopes.com/insulin.htm

  4. Tattersall R (1995) Pancreatic organotherapy for diabetes, 1889–1921. Med Hist 39(3):288–316

    Article  PubMed  CAS  Google Scholar 

  5. Schneider T (1972) Diabetes through the ages: a salute to insulin. S Afr Med J 46:1394–1400

    PubMed  CAS  Google Scholar 

  6. Rennie J, Fraser T (1907) The islets of Langerhans in relation to diabetes. Biochem J 2(1–2):7–19

    PubMed  CAS  Google Scholar 

  7. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (1922) Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 12(3):141–146

    PubMed  CAS  Google Scholar 

  8. Rosenfeld L (2002) Insulin: discovery and controversy. Clin Chem 48(12):2270–2288

    PubMed  CAS  Google Scholar 

  9. Joshi SR, Parikh RM, Das AK (2007) Insulin—history, biochemistry, physiology and pharmacology. J Assoc Phys India 55(Suppl):19–25

    Google Scholar 

  10. Jiménez JL, Nettleton EJ, Bouchard M, Robinson CV, Dobson CM, Saibil HR (2002) The protofilament structure of insulin amyloid fibrils. Proc Natl Acad Sci 99(14):9196–9201

    Article  PubMed  CAS  Google Scholar 

  11. Marques RG, Fontaine MJ, Rogers J (2004) C-peptide: much more than a byproduct of insulin biosynthesis. Pancreas 29(3):231–238

    Article  PubMed  CAS  Google Scholar 

  12. Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, Rossini AA, Urano F (2006) Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab 4(3):245–254. doi:10.1016/j.cmet.2006.07.007

    Article  PubMed  CAS  Google Scholar 

  13. Zeng G, Quon MJ (1996) Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98(4):894–898. doi:10.1172/JCI118871

    Article  PubMed  CAS  Google Scholar 

  14. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD (1994) Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 94(3):1172–1179. doi:10.1172/JCI117433

    Article  PubMed  CAS  Google Scholar 

  15. Chowers I, Lavy S, Halpern L (1961) Effect of insulin administered intracisternally in dogs on the glucose level of the blood and the cerebrospinal fluid. Exp Neurol 3(2):197–205

    Article  CAS  Google Scholar 

  16. Chowers I, Lavy S, Halpern L (1966) Effect of insulin administered intracisternally on the glucose level of the blood and the cerebrospinal fluid in vagotomized dogs. Exp Neurol 14(3):383–389

    Article  PubMed  CAS  Google Scholar 

  17. Woods SC, Porte D Jr (1975) Effect of intracisternal insulin on plasma glucose and insulin in the dog. Diabetes 24(10):905–909

    Article  PubMed  CAS  Google Scholar 

  18. Havrankova J, Schmechel D, Roth J, Brownstein M (1978) Identification of insulin in rat brain. Proc Natl Acad Sci U S A 75(11):5737–5741

    Article  PubMed  CAS  Google Scholar 

  19. Havrankova J, Roth J, Brownstein MJ (1979) Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents. J Clin Invest 64(2):636–642. doi:10.1172/JCI109504

    Article  PubMed  CAS  Google Scholar 

  20. Dorn A, Bernstein HG, Rinne A, Ziegler M, Hahn HJ, Ansorge S (1983) Insulin and glucagonlike peptides in the brain. Anat Rec 207(1):69–77

    Article  PubMed  CAS  Google Scholar 

  21. Dorn A, Rinne A, Bernstein H, Hahn H, Ziegler M (1983) Insulin and C-peptide in human brain neurons (insulin/C-peptide/brain peptides/immunohistochemistry/radioimmunoassay). J Hirnforsch 24(5):495–499

    PubMed  CAS  Google Scholar 

  22. Havrankova J, Roth J, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272(5656):827–829

    Article  PubMed  CAS  Google Scholar 

  23. Eng J, Yalow RS (1981) Evidence against extrapancreatic insulin synthesis. Proc Natl Acad Sci U S A 78(7):4576–4578

    Article  PubMed  CAS  Google Scholar 

  24. Plata-Salamán CR (1991) Insulin in the cerebrospinal fluid. Neurosci Biobehav Rev 15(2):243–258

    Article  PubMed  Google Scholar 

  25. Cucullo L, Hossain M, Puvenna V, Marchi N, Janigro D (2011) The role of shear stress in blood–brain barrier endothelial physiology. BMC Neurosci 12:40. doi:10.1186/1471-2202-12-40

    Article  PubMed  CAS  Google Scholar 

  26. Banks WA (2005) Blood–brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 11(8):973–984

    Article  PubMed  CAS  Google Scholar 

  27. Banks WA (2004) The source of cerebral insulin. Eur J Pharmacol 490(1–3):5–12. doi:10.1016/j.ejphar.2004.02.040

    Article  PubMed  CAS  Google Scholar 

  28. Banks WA, Kastin AJ (1996) Passage of peptides across the blood–brain barrier: pathophysiological perspectives. Life Sci 59(23):1923–1943

    Article  PubMed  CAS  Google Scholar 

  29. Margolis RU, Altszuler N (1967) Insulin in the cerebrospinal fluid. Nature 215:1375–1376

    Article  PubMed  CAS  Google Scholar 

  30. Woods SC, Porte D (1977) Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am J Physiol Gastrointest Liver Physiol 233(4):G331–G334

    Google Scholar 

  31. Banks WA, Jaspan JB, Huang W, Kastin AJ (1997) Transport of insulin across the blood–brain barrier: saturability at euglycemic doses of insulin. Peptides 18(9):1423–1429

    Article  PubMed  CAS  Google Scholar 

  32. Duffy KR, Pardridge WM (1987) Blood–brain barrier transcytosis of insulin in developing rabbits. Brain Res 420(1):32–38

    Article  PubMed  CAS  Google Scholar 

  33. Pardridge WM, Eisenberg J, Yang J (1985) Human blood–brain barrier insulin receptor. J Neurochem 44(6):1771–1778

    Article  PubMed  CAS  Google Scholar 

  34. Frank H, Pardridge W (1981) A direct in vitro demonstration of insulin binding to isolated brain microvessels. Diabetes 30(9):757–761

    Article  PubMed  CAS  Google Scholar 

  35. Baura GD, Foster D, Porte D Jr, Kahn S, Bergman R, Cobelli C, Schwartz M (1993) Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Investig 92(4):1824–1830

    Article  PubMed  CAS  Google Scholar 

  36. Banks WA, Kastin AJ (1998) Differential permeability of the blood–brain barrier to two pancreatic peptides: insulin and amylin. Peptides 19(5):883–889

    Article  PubMed  CAS  Google Scholar 

  37. Baura G, Foster D, Kaiyala K, Porte D, Kahn S, Schwartz M (1996) Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs. Diabetes 45(1):86–90

    Article  PubMed  CAS  Google Scholar 

  38. Banks WA, Jaspan JB, Kastin AJ (1997) Effect of diabetes mellitus on the permeability of the blood–brain barrier to insulin. Peptides 18(10):1577–1584

    Article  PubMed  CAS  Google Scholar 

  39. Frank H, Jankovic-Vokes T, Pardridge W, Morris W (1985) Enhanced insulin binding to blood–brain barrier in vivo and to brain microvessels in vitro in newborn rabbits. Diabetes 34(8):728–733

    Article  PubMed  CAS  Google Scholar 

  40. Strubbe J, Porte D Jr, Woods S (1988) Insulin responses and glucose levels in plasma and cerebrospinal fluid during fasting and refeeding in the rat. Physiol Behav 44(2):205–208

    Article  PubMed  CAS  Google Scholar 

  41. Florant G, Richardson R, Mahan S, Singer L, Woods S (1991) Seasonal changes in CSF insulin levels in marmots: insulin may not be a satiety signal for fasting in winter. Am J Physiol Regul Integr Comp Physiol 260(4):R712–R716

    CAS  Google Scholar 

  42. Kaiyala KJ, Prigeon RL, Kahn SE, Woods SC, Schwartz MW (2000) Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49(9):1525–1533

    Article  PubMed  CAS  Google Scholar 

  43. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Türk A, Hoyer S (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm 105(4):423–438

    Article  PubMed  Google Scholar 

  44. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr (1998) Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50(1):164–168

    Article  PubMed  CAS  Google Scholar 

  45. Xaio H, Banks W, Niehoff ML, Morley J (2001) Effect of LPS on the permeability of the blood–brain barrier to insulin. Brain Res 896(1–2):36–42

    Article  PubMed  CAS  Google Scholar 

  46. Dorn A, Rinne A, Hahn HJ, Bernstein HG, Ziegler M (1982) C-peptide immunoreactive neurons in human brain. Acta Histochemica 70(2):326–330

    Article  PubMed  CAS  Google Scholar 

  47. Jezov D, Vigas M, Sadlon J (1985) C-peptide-like material in rat brain: response to fasting and glucose ingestion. Endocrinol Exp 19(4):261–266

    Google Scholar 

  48. Birch NP, Christie DL, Renwick AGC (1984) Proinsulin-like material in mouse foetal brain cell cultures. FEBS Lett 168(2):299–302

    Article  PubMed  CAS  Google Scholar 

  49. Gerozissis K (2003) Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol 23(1):1–25

    Article  PubMed  Google Scholar 

  50. Devaskar SU, Singh BS, Carnaghi LR, Rajakumar PA, Giddings SJ (1993) Insulin II gene expression in rat central nervous system. Regul Pept 48(1–2):55–63

    Article  PubMed  CAS  Google Scholar 

  51. Young WS III (1986) Periventricular hypothalamic cells in the rat brain contain insulin mRNA. Neuropeptides 8(2):93–97

    Article  PubMed  CAS  Google Scholar 

  52. Schechter R, Whitmire J, Wheet GS, Beju D, Jackson KW, Harlow R, Gavin JR III (1994) Immunohistochemical and in situ hybridization study of an insulin-like substance in fetal neuron cell cultures. Brain Res 636(1):9–27

    Article  PubMed  CAS  Google Scholar 

  53. Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L (1996) Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res 736(1–2):16–27

    Article  PubMed  CAS  Google Scholar 

  54. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS (1994) Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem 269(11):8445–8454

    PubMed  CAS  Google Scholar 

  55. Schechter R, Holtzclaw L, Sadiq F, Kahn A, Devaskar S (1988) Insulin synthesis by isolated rabbit neurons. Endocrinology 123(1):505–513

    Article  PubMed  CAS  Google Scholar 

  56. Clarke DW, Mudd L, Boyd FT Jr, Fields M, Raizada MK (1986) Insulin is released from rat brain neuronal cells in culture. J Neurochem 47(3):831–836

    Article  PubMed  CAS  Google Scholar 

  57. Singh BS (1997) Insulin gene expression in immortalized rat hippocampal and pheochromocytoma-12 cell lines1. Regul Pept 69(1):7–14

    Article  PubMed  CAS  Google Scholar 

  58. Raizada MK (1983) Localization of insulin-like immunoreactivity in the neurons from primary cultures of rat brain. Exp Cell Res 143(2):351–357

    Article  PubMed  CAS  Google Scholar 

  59. Santos MS, Pereira EM, Carvaho AP (1999) Stimulation of immunoreactive insulin release by glucose in rat brain synaptosomes. Neurochem Res 24(1):33–36

    Article  PubMed  CAS  Google Scholar 

  60. Madadi G, Dalvi PS, Belsham DD (2008) Regulation of brain insulin mRNA by glucose and glucagon-like peptide 1. Biochem Biophys Res Commun 376(4):694–699

    Article  PubMed  CAS  Google Scholar 

  61. Szabo O, Szabo AJ (1972) Evidence for an insulin-sensitive receptor in the central nervous system. Am J Physiol--Legacy Content 223(6):1349–1353

    CAS  Google Scholar 

  62. Posner BI, Kelly PA, Shiu RP, Friesen HG (1974) Studies of insulin, growth hormone and prolactin binding: tissue distribution, species variation and characterization. Endocrinology 95(2):521–531

    Article  PubMed  CAS  Google Scholar 

  63. van Houten M, Posner BI, Kopriwa BM, Brawer JR (1979) Insulin-binding sites in the rat brain: in vivo localization to the circumventricular organs by quantitative radioautography. Endocrinology 105(3):666–673

    Article  PubMed  Google Scholar 

  64. Kappy MS, Raizada MK (1982) Adult-level insulin binding is present in term fetal rat CNS membranes. Brain Res 249(2):390–392

    Article  PubMed  CAS  Google Scholar 

  65. Pacold S, Blackard W (1979) Central nervous system insulin receptors in normal and diabetic rats. Endocrinology 105(6):1452–1457

    Article  PubMed  CAS  Google Scholar 

  66. Landau B, Takaoka Y, Abrams M, Genuth S, Van Houten M, Posner B, White R, Ohgaku S, Horvat A, Hemmelgarn E (1983) Binding of insulin by monkey and pig hypothalamus. Diabetes 32(3):284–291

    Article  PubMed  CAS  Google Scholar 

  67. Waldbillig RJ, LeRoith D (1987) Insulin receptors in the peripheral nervous system: a structural and functional analysis. Brain Res 409(2):215–220

    Article  PubMed  CAS  Google Scholar 

  68. Hill J, Lesniak M, Pert C, Roth J (1986) Autoradiographic localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience 17(4):1127–1138

    Article  PubMed  CAS  Google Scholar 

  69. Schulingkamp R, Pagano T, Hung D, Raffa R (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24(8):855–872

    Article  PubMed  CAS  Google Scholar 

  70. Havrankova J, Brownstein M, Roth J (1981) Insulin and insulin receptors in rodent brain. Diabetologia 20(3):268–273

    Article  PubMed  CAS  Google Scholar 

  71. Mielke J, Wang Y (2011) Insulin, synaptic function, and opportunities for neuroprotection. Prog Mol Biol Transl Sci 98:133–186

    Article  PubMed  CAS  Google Scholar 

  72. Hopkins D, Williams G (1997) Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med 14(12):1044–1050

    Article  PubMed  CAS  Google Scholar 

  73. Marks JL, Porte D, Stahl WL, Baskin DG (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127(6):3234–3236

    Article  PubMed  CAS  Google Scholar 

  74. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, Mendelsohn FA (1987) Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121(4):1562–1570

    Article  PubMed  CAS  Google Scholar 

  75. Abbott M, Wells D, Fallon J (1999) The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci: Official J Soc Neurosci 19(17):7300–7308

    CAS  Google Scholar 

  76. Hoersch D, Kahn CR (1999) Region specific mRNA expression of phosphatidylinositol 3 kinase regulatory isoforms in the central nervous system of C57BL/6J mice. J Comp Neurol 415(1):105–120

    Article  Google Scholar 

  77. Moss A, Unger J, Moxley R, Livingston J (1990) Location of phosphotyrosine-containing proteins by immunocytochemistry in the rat forebrain corresponds to the distribution of the insulin receptor. Proc Natl Acad Sci 87(12):4453–4457

    Article  PubMed  CAS  Google Scholar 

  78. Unger J, Moss A, Livingston J (1991) Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience 42(3):853–861

    Article  PubMed  CAS  Google Scholar 

  79. Potau N, Escofet M, Martinez M (1991) Ontogenesis of insulin receptors in human cerebral cortex. J Endocrinol Investig 14(1):53–58

    CAS  Google Scholar 

  80. Zaia A, Piantanelli L (1996) Alterations of brain insulin receptor characteristics in aging mice. Arch Gerontol Geriatr 23(1):27–37

    Article  PubMed  CAS  Google Scholar 

  81. Zaia A, Piantanelli L (2000) Insulin receptors in the brain cortex of aging mice. Mech Ageing Dev 113(3):227–232

    Article  PubMed  CAS  Google Scholar 

  82. Brennan W Jr (1988) Developmental aspects of the rat brain insulin receptor: loss of sialic acid and fluctuation in number characterize fetal development. Endocrinology 122(6):2364–2370

    Article  PubMed  CAS  Google Scholar 

  83. Tchilian E, Zhelezarov I, Petkov V, Hadjiivanova CI (1990) 125I-insulin binding is decreased in olfactory bulbs of aged rats. Neuropeptides 17(4):193–196

    Article  PubMed  CAS  Google Scholar 

  84. LeRoith D, Lowe WL Jr, Shemer J, Raizada MK, Ota A (1988) Development of brain insulin receptors. Int J Biochem 20(3):225–230

    Article  PubMed  CAS  Google Scholar 

  85. Zahniser NR, Goens MB, Hanaway PJ, Vinych JV (1984) Characterization and regulation of insulin receptors in rat brain. J Neurochem 42(5):1354–1362

    Article  PubMed  CAS  Google Scholar 

  86. Heidenreich KA, Zahniser NR, Berhanu P, Brandenburg D, Olefsky JM (1983) Structural differences between insulin receptors in the brain and peripheral target tissues. J Biol Chem 258(14):8527–8530

    PubMed  CAS  Google Scholar 

  87. Yip CC, Moule ML, Yeung CWT (1980) Characterization of insulin receptor subunits in brain and other tissues by photoaffinity labeling. Biochem Biophys Res Commun 96(4):1671–1678

    Article  PubMed  CAS  Google Scholar 

  88. Boyd F, Raizada MK (1983) Effects of insulin and tunicamycin on neuronal insulin receptors in culture. Am J Physiol-Cell Physiol 245(3):C283–C287

    CAS  Google Scholar 

  89. Taha C, Klip A (1999) The insulin signaling pathway. J Membr Biol 169(1):1–12

    Article  PubMed  CAS  Google Scholar 

  90. Brummer T, Schmitz-Peiffer C, Daly RJ (2010) Docking proteins. FEBS J 277(21):4356–4369

    Article  PubMed  CAS  Google Scholar 

  91. Boura-Halfon S, Zick Y (2009) Chapter 12 serine kinases of insulin receptor substrate proteins. In: Gerald L (ed) Vitamins and hormones, vol. 80. Academic, London, pp 313–349

    Google Scholar 

  92. van der Heide LP, Ramakers GMJ, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79(4):205–221

    Article  PubMed  CAS  Google Scholar 

  93. Sun XJ, Miralpeix M, Myers M, Glasheen E, Backer J, Kahn C, White M (1992) Expression and function of IRS-1 in insulin signal transmission. J Biol Chem 267(31):22662–22672

    PubMed  CAS  Google Scholar 

  94. Baskin DG, Sipols AJ, Schwartz MW, White MF (1993) Immunocytochemical detection of insulin receptor substrate-1 (IRS-1) in rat brain: colocalization with phosphotyrosine. Regul Pept 48(1–2):257–266

    Article  PubMed  CAS  Google Scholar 

  95. Baskin DG, Schwartz MW, Sipols AJ, D'Alessio DA, Goldstein BJ, White MF (1994) Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology 134(4):1952–1955

    Article  PubMed  CAS  Google Scholar 

  96. Porte D, Baskin DG, Schwartz MW (2005) Insulin signaling in the central nervous system. Diabetes 54(5):1264–1276

    Article  PubMed  CAS  Google Scholar 

  97. Torsoni MA, Carvalheira JB, Pereira-Da-Silva M, de Carvalho-Filho MA, Saad MJA, Velloso LA (2003) Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold. Am J Physiol-Endocrinol Metabolism 285(1):E216–E223

    CAS  Google Scholar 

  98. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF (2004) Dysregulation of insulin receptor substrate 2 in cells and brain causes obesity and diabetes. J Clin Investig 114(7):908–916

    PubMed  CAS  Google Scholar 

  99. Shen L, Wang DQ, Tso P, Jandacek RJ, Woods SC, Liu M (2011) Apolipoprotein E reduces food intake via PI3K/Akt signaling pathway in the hypothalamus. Physiol Behav 105(1):124–128. doi:10.1016/j.physbeh.2011.04.018

    Article  PubMed  CAS  Google Scholar 

  100. McGowan MK, Andrews KM, Grossman SP (1992) Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol Behav 51(4):753–766

    Article  PubMed  CAS  Google Scholar 

  101. Gerozissis K (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585(1):38–49

    Article  PubMed  CAS  Google Scholar 

  102. Schwartz MW, Porte D (2005) Diabetes, obesity, and the brain. Science 307(5708):375–379

    Article  PubMed  CAS  Google Scholar 

  103. Fehm H, Kern W, Peters A (2006) The selfish brain: competition for energy resources. Progress Brain Res 153:129–140

    Article  CAS  Google Scholar 

  104. Morton G, Cummings D, Baskin D, Barsh G, Schwartz M (2006) Central nervous system control of food intake and body weight. Nat-Lond 443(7109):289–295

    Article  CAS  Google Scholar 

  105. Stockhorst U, de Fries D, Steingrueber HJ, Scherbaum WA (2004) Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol Behav 83(1):47–54

    PubMed  CAS  Google Scholar 

  106. Gerozissis K (2004) Brain insulin and feeding: a bi-directional communication. Eur J Pharmacol 490(1–3):59–70

    Article  PubMed  CAS  Google Scholar 

  107. Woods SC, Lotter EC, McKay LD, Porte D Jr (1979) Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282(5738):503–505

    Article  PubMed  CAS  Google Scholar 

  108. Brief DJ, Davis JD (1984) Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res Bull 12(5):571–575

    Article  PubMed  CAS  Google Scholar 

  109. Foster L, Ames N, Emery R (1991) Food intake and serum insulin responses to intraventricular infusions of insulin and IGF-I. Physiol Behav 50(4):745–749

    Article  PubMed  CAS  Google Scholar 

  110. Chavez M, Riedy CA, Van Dijk G, Woods SC (1996) Central insulin and macronutrient intake in the rat. Am J Physiol Regul Integr Comp Physiol 271(3):R727–R731

    CAS  Google Scholar 

  111. Destefano MB, Stern JS, Castonguay TW (1991) Effect of chronic insulin administration on food intake and body weight in rats. Physiol Behav 50(4):801–806

    Article  PubMed  CAS  Google Scholar 

  112. Honda K, Kamisoyama H, Saneyasu T, Sugahara K, Hasegawa S (2007) Central administration of insulin suppresses food intake in chicks. Neurosci Lett 423(2):153–157

    Article  PubMed  CAS  Google Scholar 

  113. Brown LM, Clegg DJ, Benoit SC, Woods SC (2006) Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice. Physiol Behav 89(5):687–691

    Article  PubMed  CAS  Google Scholar 

  114. Air EL, Benoit SC, Blake Smith KA, Clegg DJ, Woods SC (2002) Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol Biochem Behav 72(1–2):423–429

    Article  PubMed  CAS  Google Scholar 

  115. Hatfield JS, Millard WJ, Smith C (1974) Short-term influence of intra-ventromedial hypothalamic administration of insulin on feeding in normal and diabetic rats. Pharmacol Biochem Behav 2(2):223–226

    Article  PubMed  CAS  Google Scholar 

  116. Clegg DJ, Riedy CA, Smith KAB, Benoit SC, Woods SC (2003) Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52(3):682–687

    Article  PubMed  CAS  Google Scholar 

  117. Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8(12):1376–1382

    Article  PubMed  CAS  Google Scholar 

  118. Strubbe J, Mein C (1977) Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol Behav 19(2):309–313

    Article  PubMed  CAS  Google Scholar 

  119. Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Müller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289(5487):2122–2125

    Article  PubMed  Google Scholar 

  120. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L (2002) Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci 5(6):566–572

    Article  PubMed  CAS  Google Scholar 

  121. Havel PJ (2001) Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med 226(11):963–977

    CAS  Google Scholar 

  122. Hallschmid M, Benedict C, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin reduces body fat in men but not in women. Diabetes 53(11):3024–3029

    Article  PubMed  CAS  Google Scholar 

  123. Fernandez-Fernandez R, Martini A, Navarro V, Castellano J, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M (2006) Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol 254:127–132

    Article  PubMed  CAS  Google Scholar 

  124. Smith MS, True C, Grove KL (2010) The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin. Brain Res 1364:139–152. doi:10.1016/j.brainres.2010.08.038

    Article  PubMed  CAS  Google Scholar 

  125. Castellano J, Roa J, Luque R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M (2009) KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides 30(1):139–145

    Article  PubMed  CAS  Google Scholar 

  126. Castellano J, Navarro V, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez M, Vigo E, Casanueva F, Aguilar E (2005) Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 146(9):3917–3925

    Article  PubMed  CAS  Google Scholar 

  127. Crown A, Clifton DK, Steiner RA (2007) Neuropeptide signaling in the integration of metabolism and reproduction. Neuroendocrinology 86(3):175–182

    Article  PubMed  CAS  Google Scholar 

  128. Hill JW, Elmquist JK, Elias CF (2008) Hypothalamic pathways linking energy balance and reproduction. Am J Physiol-Endocrinol Metab 294(5):E827–E832

    Article  PubMed  CAS  Google Scholar 

  129. Schneider JE (2004) Energy balance and reproduction. Physiol Behav 81(2):289–317

    Article  PubMed  CAS  Google Scholar 

  130. Arias P, Rodriguez M, Szwarcfarb B, Sinay I, Moguilevsky J (1992) Effect of insulin on LHRH release by perifused hypothalamic fragments. Neuroendocrinology 56(3):415–418

    Article  PubMed  CAS  Google Scholar 

  131. Miller D, Blache D, Martin G (1995) The role of intracerebral insulin in the effect of nutrition on gonadotrophin secretion in mature male sheep. J Endocrinol 147(2):321–329

    Article  PubMed  CAS  Google Scholar 

  132. Dong Q, Lazarus R, Wong L, Vellios M, Handelsman D (1991) Pulsatile LH secretion in streptozotocin-induced diabetes in the rat. J Endocrinol 131(1):49–55

    Article  PubMed  CAS  Google Scholar 

  133. Bucholtz DC, Chiesa A, Pappano WN, Nagatani S, Tsukamura H, Maeda KI, Foster DL (2000) Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic male lamb. Biol Reprod 62(5):1248–1255

    Article  PubMed  CAS  Google Scholar 

  134. Tanaka T, Nagatani S, Bucholtz DC, Ohkura S, Tsukamura H, Maeda KI, Foster DL (2000) Central action of insulin regulates pulsatile luteinizing hormone secretion in the diabetic sheep model. Biol Reprod 62(5):1256–1261

    Article  PubMed  CAS  Google Scholar 

  135. Hileman S, Schillo K, Hall J (1993) Effects of acute, intracerebroventricular administration of insulin on serum concentrations of luteinizing hormone, insulin, and glucose in ovariectomized lambs during restricted and ad libitum feed intake. Biol Reprod 48(1):117–124

    Article  PubMed  CAS  Google Scholar 

  136. Williams NI, Lancas MJ, Cameron JL (1996) Stimulation of luteinizing hormone secretion by food intake: evidence against a role for insulin. Endocrinology 137(6):2565–2571

    Article  PubMed  CAS  Google Scholar 

  137. van Houten M, Posner BI, Kopriwa BM (1980) Insulin binding sites localized to nerve terminals in rat median eminence and arcuate nucleus. Science 207(4435):1081–1083

    Article  PubMed  Google Scholar 

  138. Masters BA, Shemer J, Judkins JH, Clarke DW, Roith DL, Raizada MK (1987) Insulin receptors and insulin action in dissociated brain cells. Brain Res 417(2):247–256

    Article  PubMed  CAS  Google Scholar 

  139. Allen KV, Frier BM, Strachan MWJ (2004) The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. Eur J Pharmacol 490(1–3):169–175

    Article  PubMed  CAS  Google Scholar 

  140. Hershey T, Craft S, Bhargava N, White NH (1997) Memory and insulin dependent diabetes mellitus (IDDM): effects of childhood onset and severe hypoglycemia. J Int Neuropsychol Soc 3(6):509–520

    PubMed  CAS  Google Scholar 

  141. Reaven G, Thompson L, Nahum D, Haskins E (1990) Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 13(1):16–21

    Article  PubMed  CAS  Google Scholar 

  142. Elias P, Elias M, D'Agostino R, Cupples L, Wilson P, Silbershatz H, Wolf P (1997) NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham Study. Diabetes Care 20(9):1388–1395

    Article  PubMed  CAS  Google Scholar 

  143. Stewart R, Liolitsa D (1999) Type 2 diabetes mellitus, cognitive impairment and dementia. Diabet Med 16(2):93–112

    Article  PubMed  CAS  Google Scholar 

  144. Ryan CM, Geckle M (2000) Why is learning and memory dysfunction in type 2 diabetes limited to older adults? Diabetes Metab Res Rev 16(5):308–315

    Article  PubMed  CAS  Google Scholar 

  145. Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL (2002) Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 5(6):514–516

    Article  PubMed  CAS  Google Scholar 

  146. Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J, Kern W (2006) Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32(1):239–243

    Article  PubMed  CAS  Google Scholar 

  147. Fan X, Copeland PM, Liu EY, Chiang E, Freudenreich O, Goff DC, Henderson DC (2011) No effect of single-dose intranasal insulin treatment on verbal memory and sustained attention in patients with schizophrenia. J Clin Psychopharmacol 31(2):231–234. doi:10.1097/JCP.0b013e31820ebd0e

    Article  PubMed  CAS  Google Scholar 

  148. Reger M, Watson G, Frey I, Baker L, Cholerton B, Keeling M, Belongia D, Fishel M, Plymate S, Schellenberg G (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27(3):451–458

    Article  PubMed  CAS  Google Scholar 

  149. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10):1326–1334

    Article  PubMed  CAS  Google Scholar 

  150. Hallschmid M, Benedict C, Schultes B, Born J, Kern W (2007) Obese men respond to cognitive but not to catabolic brain insulin signaling. Int J Obes 32(2):275–282

    Article  CAS  Google Scholar 

  151. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13(3):323–331

    PubMed  CAS  Google Scholar 

  152. Benedict C, Kern W, Schultes B, Born J, Hallschmid M (2008) Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab 93(4):1339–1344

    Article  PubMed  CAS  Google Scholar 

  153. Krug R, Benedict C, Born J, Hallschmid M (2010) Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J Clin Endocrinol Metab 95(12):E468–E472

    Article  PubMed  CAS  Google Scholar 

  154. Kopf SR, Boccia MM, Baratti CM (1998) AF-DX 116, a presynaptic muscarinic receptor antagonist, potentiates the effects of glucose and reverses the effects of insulin on memory. Neurobiol Learn Mem 70(3):305–313

    Article  PubMed  CAS  Google Scholar 

  155. Kopf SR, Baratti CM (1999) Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem 71(1):50–61

    Article  PubMed  CAS  Google Scholar 

  156. Akanmu MA, Nwabudike NL, Ilesanmi OR (2009) Analgesic, learning and memory and anxiolytic effects of insulin in mice. Behav Brain Res 196(2):237–241. doi:10.1016/j.bbr.2008.09.008

    Article  PubMed  CAS  Google Scholar 

  157. Kopf SR, Baratti CM (1996) Memory modulation by post-training glucose or insulin remains evident at long retention intervals. Neurobiol Learn Mem 65(2):189–191. doi:10.1006/nlme.1996.0020

    Article  PubMed  CAS  Google Scholar 

  158. Kopf SR, Baratti CM (1996) Effects of posttraining administration of glucose on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem 65(3):253–260

    Article  PubMed  CAS  Google Scholar 

  159. Kopf SR, Baratti CM (1995) The impairment of retention induced by insulin in mice may be mediated by a reduction in central cholinergic activity. Neurobiol Learn Mem 63(3):220–228

    Article  PubMed  CAS  Google Scholar 

  160. Kern W, Peters A, Fruehwald-Schultes B, Deininger E, Born J, Fehm HL (2000) Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 74(4):270–280

    Article  Google Scholar 

  161. Jafari MR, Zarrindast MR, Djahanguiri B (2004) Effects of different doses of glucose and insulin on morphine state-dependent memory of passive avoidance in mice. Psychopharmacol (Berl) 175(4):457–462. doi:10.1007/s00213-004-1841-7

    CAS  Google Scholar 

  162. Park CR, Seeley RJ, Craft S, Woods SC (2000) Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 68(4):509–514

    Article  PubMed  CAS  Google Scholar 

  163. Schwarzberg H, Bernstein HG, Reiser M, Günther O (1989) Intracerebroventricular administration of insulin attenuates retrieval of a passive avoidance response in rats. Neuropeptides 13(2):79–81

    Article  PubMed  CAS  Google Scholar 

  164. Haj-ali V, Mohaddes G, Babri S (2009) Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behav Neurosci 123(6):1309–1314

    Article  PubMed  CAS  Google Scholar 

  165. Babri S, Badie HG, Khamenei S, Ordikhani-Seyedlar M (2007) Intrahippocampal insulin improves memory in a passive-avoidance task in male wistar rats. Brain Cogn 64(1):86–91

    Article  PubMed  Google Scholar 

  166. Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S (2006) The effect of intrahippocampal insulin microinjection on spatial learning and memory. Horm Behav 50(5):748–752

    Article  PubMed  CAS  Google Scholar 

  167. Moosavi M, Naghdi N, Choopani S (2007) Intra CA1 insulin microinjection improves memory consolidation and retrieval. Peptides 28(5):1029–1034

    Article  PubMed  CAS  Google Scholar 

  168. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS (2010) Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 93(4):546–553. doi:10.1016/j.nlm.2010.02.002

    Article  PubMed  CAS  Google Scholar 

  169. Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S (2007) Insulin protects against stress-induced impairments in water maze performance. Behav Brain Res 176(2):230–236

    Article  PubMed  CAS  Google Scholar 

  170. Blanchard JG, Duncan PM (1997) Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacol Biochem Behav 58(1):209–214

    Article  PubMed  CAS  Google Scholar 

  171. Lin CH, Tomioka M, Pereira S, Sellings L, Iino Y, van der Kooy D (2010) Insulin signaling plays a dual role in Caenorhabditis elegans memory acquisition and memory retrieval. J Neurosci 30(23):8001–8011. doi:10.1523/JNEUROSCI.4636-09.2010

    Article  PubMed  CAS  Google Scholar 

  172. Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ (2005) Insulin receptor signaling in long-term memory consolidation following spatial learning. Learn Mem 12(6):646–655. doi:10.1101/lm.88005

    Article  PubMed  Google Scholar 

  173. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. J Biol Chem 274(49):34893–34902

    Article  PubMed  CAS  Google Scholar 

  174. Martin ED, Sanchez-Perez A, Trejo JL, Martin-Aldana JA, Cano Jaimez M, Pons S, Acosta Umanzor C, Menes L, White MF, Burks DJ (2011) IRS-2 deficiency impairs NMDA receptor-dependent long-term potentiation. Cereb Cortex 22(8):1717–1727. doi:10.1093/cercor/bhr216

    Article  PubMed  Google Scholar 

  175. Lee CC, Kuo YM, Huang CC, Hsu KS (2009) Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiol Aging 30(3):377–387. doi:10.1016/j.neurobiolaging.2007.06.014

    Article  PubMed  CAS  Google Scholar 

  176. Izumi Y, Yamada KA, Matsukawa M, Zorumski CF (2003) Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats. Diabetologia 46(7):1007–1012. doi:10.1007/s00125-003-1144-2

    Article  PubMed  CAS  Google Scholar 

  177. Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE, Sheng M, Wang YT (2000) Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25(3):649–662

    Article  PubMed  CAS  Google Scholar 

  178. Van Der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GMJ (2005) Insulin modulates hippocampal activity dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl inositol 3 kinase dependent manner. J Neurochem 94(4):1158–1166

    Article  PubMed  CAS  Google Scholar 

  179. Park C (2001) Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25(4):311–323

    Article  PubMed  CAS  Google Scholar 

  180. Henneberg N, Hoyer S (1994) Short-term or long-term intracerebroventricular (i.c.v.) infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Lett 175(1–2):153–156

    Article  PubMed  CAS  Google Scholar 

  181. Hoyer S, Henneberg N, Knapp S, Lannert H, Martin E (1996) Brain glucose metabolism is controlled by amplification and desensitization of the neuronal insulin receptor. Ann N Y Acad Sci 777(1):374–379

    Article  PubMed  CAS  Google Scholar 

  182. Vannucci SJ, Koehler-Stec EM, Li K, Reynolds TH, Clark R, Simpson IA (1998) GLUT4 glucose transporter expression in rodent brain: effect of diabetes. Brain Res 797(1):1–11

    Article  PubMed  CAS  Google Scholar 

  183. Messier C, White NM (1987) Memory improvement by glucose, fructose, and two glucose analogs: a possible effect on peripheral glucose transport. Behav Neural Biol 48(1):104–127

    Article  PubMed  CAS  Google Scholar 

  184. Gold PE, Vogt JA, Hall JL (1986) Glucose effects on memory: behavioral and pharmacological characteristics1. Behav Neural Biol 46(2):145–155

    Article  PubMed  CAS  Google Scholar 

  185. Hall JL, Gonder-Frederick L, Chewning W, Silveira J, Gold P (1989) Glucose enhancement of performance of memory tests in young and aged humans. Neuropsychologia 27(9):1129–1138

    Article  PubMed  CAS  Google Scholar 

  186. Lee MK, Graham SN, Gold PE (1988) Memory enhancement with posttraining intraventricular glucose injections in rats. Behav Neurosci 102(4):591–595

    Article  PubMed  CAS  Google Scholar 

  187. Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490(1–3):71–81

    Article  PubMed  CAS  Google Scholar 

  188. Liu L, Brown JC (1995) Insulin potentiates N-methyl-d-aspartate receptor activity in Xenopus oocytes and rat hippocampus. Neurosci Lett 192(1):5–8

    Article  PubMed  CAS  Google Scholar 

  189. Liao GY, Leonard JP (1999) Insulin modulation of cloned mouse NMDA receptor currents in Xenopus oocytes. J Neurochem 73(4):1510–1519

    Article  PubMed  CAS  Google Scholar 

  190. Chen S, Leonard JP (1996) Protein tyrosine kinase mediated potentiation of currents from cloned NMDA receptors. J Neurochem 67(1):194–200

    Article  PubMed  CAS  Google Scholar 

  191. Christie J, Wenthold R, Monaghan D (1999) Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. J Neurochem 72(4):1523–1528

    Article  PubMed  CAS  Google Scholar 

  192. Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MVL (2001) Insulin promotes rapid delivery of N-methyl-d-aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci 98(6):3561–3566

    Article  PubMed  CAS  Google Scholar 

  193. Jin SX, Feig LA (2010) Long-term potentiation in the CA1 hippocampus induced by NR2A subunit-containing NMDA glutamate receptors is mediated by Ras-GRF2/Erk map kinase signaling. PLoS One 5(7):e11732. doi:10.1371/journal.pone.0011732

    Article  PubMed  CAS  Google Scholar 

  194. Plitzko D, Rumpel S, Gottmann K (2001) Insulin promotes functional induction of silent synapses in differentiating rat neocortical neurons. Eur J Neurosci 14(8):1412–1415

    Article  PubMed  CAS  Google Scholar 

  195. Ormond J, Woodin MA (2011) Disinhibition-mediated LTP in the hippocampus is synapse specific. Front Cell Neurosci 5:17. doi:10.3389/fncel.2011.00017

    Article  PubMed  CAS  Google Scholar 

  196. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388(6643):686–690. doi:10.1038/41792

    Article  PubMed  CAS  Google Scholar 

  197. Choopani S, Moosavi M, Naghdi N (2008) Involvement of nitric oxide in insulin induced memory improvement. Peptides 29(6):898–903

    Article  PubMed  CAS  Google Scholar 

  198. Kovacs P, Hajnal A (2009) In vivo electrophysiological effects of insulin in the rat brain. Neuropeptides 43(4):283–293. doi:10.1016/j.npep. 2009.05.006

    Article  PubMed  CAS  Google Scholar 

  199. Plum L, Schubert M, Bruning JC (2005) The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 16(2):59–65. doi:10.1016/j.tem.2005.01.008

    Article  PubMed  CAS  Google Scholar 

  200. Palovcik RA, Phillips MI, Kappy MS, Raizada MK (1984) Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res 309(1):187–191

    Article  PubMed  CAS  Google Scholar 

  201. Takei H, Fujita S, Shirakawa T, Koshikawa N, Kobayashi M (2010) Insulin facilitates repetitive spike firing in rat insular cortex via phosphoinositide 3-kinase but not mitogen activated protein kinase cascade. Neuroscience 170(4):1199–1208. doi:10.1016/j.neuroscience.2010.07.061

    Article  PubMed  CAS  Google Scholar 

  202. Williams DB (2008) A novel, rapid, inhibitory effect of insulin on alpha1beta2gamma2s gamma-aminobutyric acid type A receptors. Neurosci Lett 443(1):27–31. doi:10.1016/j.neulet.2008.07.038

    Article  PubMed  CAS  Google Scholar 

  203. Vetiska S, Ahmadian G, Ju W, Liu L, Wymann M, Wang Y (2007) GABAA receptor-associated phosphoinositide 3-kinase is required for insulin-induced recruitment of postsynaptic GABAA receptors. Neuropharmacology 52(1):146–155

    Article  PubMed  CAS  Google Scholar 

  204. Ma XH, Zhong P, Gu Z, Feng J, Yan Z (2003) Muscarinic potentiation of GABA(A) receptor currents is gated by insulin signaling in the prefrontal cortex. J Neurosci 23(4):1159–1168

    PubMed  CAS  Google Scholar 

  205. Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT (2003) Control of synaptic strength, a novel function of Akt. Neuron 38(6):915–928

    Article  PubMed  CAS  Google Scholar 

  206. Fadool D, Tucker K, Phillips J, Simmen J (2000) Brain insulin receptor causes activity-dependent current suppression in the olfactory bulb through multiple phosphorylation of Kv1.3. J Neurophysiol 83(4):2332–2348

    PubMed  CAS  Google Scholar 

  207. Spanswick D, Smith M, Mirshamsi S, Routh V, Ashford M (2000) Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci 3:757–758

    Article  PubMed  CAS  Google Scholar 

  208. Brodsky JL (1990) Insulin activation of brain Na(+)-K(+)-ATPase is mediated by alpha 2-form of enzyme. Am J Physiol 258(5 Pt 1):C812–C817

    PubMed  CAS  Google Scholar 

  209. Jonas EA, Knox RJ, Smith TC, Wayne NL, Connor JA, Kaczmarek LK (1997) Regulation by insulin of a unique neuronal Ca2+ pool and of neuropeptide secretion. Nature 385(6614):343–346. doi:10.1038/385343a0

    Article  PubMed  CAS  Google Scholar 

  210. Lozovsky DB, Kopin IJ, Saller CF (1985) Modulation of dopamine receptor supersensitivity by chronic insulin: implication in schizophrenia. Brain Res 343(1):190–193

    Article  PubMed  CAS  Google Scholar 

  211. Lozovsky D, Saller CF, Kopin IJ (1981) Dopamine receptor binding is increased in diabetic rats. Science 214(4524):1031–1033

    Article  PubMed  CAS  Google Scholar 

  212. Jones K (2000) Insulin coma therapy in schizophrenia. J R Soc Med 93(3):147–149

    PubMed  CAS  Google Scholar 

  213. Danguir J, Elghozi JL, Laude D (1984) Increased dopamine and serotonin metabolites in CSF during severe insulin-induced hypoglycemia in freely moving rats. Neurochem Int 6(1):71–75

    Article  PubMed  CAS  Google Scholar 

  214. Sauter A, Goldstein M, Engel J, Ueta K (1983) Effect of insulin on central catecholamines. Brain Res 260(2):330–333

    Article  PubMed  CAS  Google Scholar 

  215. Raizada MK, Shemer J, Judkins JH, Clarke DW, Masters BA, LeRoith D (1988) Insulin receptors in the brain: structural and physiological characterization. Neurochem Res 13(4):297–303

    Article  PubMed  CAS  Google Scholar 

  216. Masters BA, Shemer J, Judkins JH, Clarke DW, Le Roith D, Raizada MK (1987) Insulin receptors and insulin action in dissociated brain cells. Brain Res 417(2):247–256

    Article  PubMed  CAS  Google Scholar 

  217. Boyd FT Jr, Clarke DW, Muther TF, Raizada MK (1985) Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain. J Biol Chem 260(29):15880–15884

    PubMed  CAS  Google Scholar 

  218. Boyd FT Jr, Clarke DW, Raizada MK (1986) Insulin inhibits specific norepinephrine uptake in neuronal cultures from rat brain. Brain Res 398(1):1–5

    Article  PubMed  CAS  Google Scholar 

  219. Figlewicz DP, Szot P, Israel PA, Payne C, Dorsa DM (1993) Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus. Brain Res 602(1):161–164

    Article  PubMed  CAS  Google Scholar 

  220. Levin BE, Israel P, Lattemann DP (1998) Insulin selectively downregulates alpha2-adrenoceptors in the arcuate and dorsomedial nucleus. Brain Res Bull 45(2):179–181

    Article  PubMed  CAS  Google Scholar 

  221. Rhoads DE, DiRocco RJ, Osburn LD, Peterson NA, Raghupathy E (1984) Stimulation of synaptosomal uptake of neurotransmitter amino acids by insulin: possible role of insulin as a neuromodulator. Biochem Biophys Res Commun 119(3):1198–1204

    Article  PubMed  CAS  Google Scholar 

  222. Chiu SL, Chen CM, Cline HT (2008) Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58(5):708–719. doi:10.1016/j.neuron.2008.04.014

    Article  PubMed  CAS  Google Scholar 

  223. Sakaguchi T, Bray GA (1987) Intrahypothalamic injection of insulin decreases firing rate of sympathetic nerves. Proc Natl Acad Sci U S A 84(7):2012–2014

    Article  PubMed  CAS  Google Scholar 

  224. Peinado JM, Myers RD (1987) Norepinephrine release from PVN and lateral hypothalamus during perfusion with 2-DG or insulin in the sated and fasted rat. Pharmacol Biochem Behav 27(4):715–721

    Article  PubMed  CAS  Google Scholar 

  225. Rotte M, Baerecke C, Pottag G, Klose S, Kanneberg E, Heinze HJ, Lehnert H (2005) Insulin affects the neuronal response in the medial temporal lobe in humans. Neuroendocrinology 81(1):49–55. doi:10.1159/000084874

    Article  PubMed  CAS  Google Scholar 

  226. Shapiro E, Brown SD, Saltiel AR, Schwartz JH (1991) Short–term action of insulin on Aplysia neurons: generation of a possible novel modulator of ion channels. J Neurobiol 22(1):55–62

    Article  PubMed  CAS  Google Scholar 

  227. Shibata S, Liou SY, Ueki S, Oomura Y (1986) Inhibitory action of insulin on suprachiasmatic nucleus neurons in rat hypothalamic slice preparations. Physiol Behav 36(1):79–81

    Article  PubMed  CAS  Google Scholar 

  228. Figlewicz D, Szot P, Greenwood MR (1990) Insulin stimulates inositol incorporation in hippocampus of lean but not obese Zucker rats. Physiol Behav 47(2):325–330

    Article  PubMed  CAS  Google Scholar 

  229. Figlewicz DP, Szot P (1991) Insulin stimulates membrane phospholipid metabolism by enhancing endogenous alpha 1-adrenergic activity in the rat hippocampus. Brain Res 550(1):101–107

    Article  PubMed  CAS  Google Scholar 

  230. Roger LJ, Fellows RE (1980) Stimulation of ornithine decarboxylase activity by insulin in developing rat brain. Endocrinology 106(2):619–625

    Article  PubMed  CAS  Google Scholar 

  231. Farrar C, Houser CR, Clarke S (2005) Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice. Aging Cell 4(1):1–12. doi:10.1111/j.1474-9728.2004.00136.x

    Article  PubMed  CAS  Google Scholar 

  232. Schubert M, Brazil D, Burks D, Kushner J, Ye J, Flint C, Farhang-Fallah J, Dikkes P, Warot X, Rio C (2003) Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci: Official J Soc Neurosci 23(18):7084–7092

    CAS  Google Scholar 

  233. Xu J, Yeon JE, Chang H, Tison G, Chen GJ, Wands J, de la Monte S (2003) Ethanol impairs insulin-stimulated neuronal survival in the developing brain. J Biol Chem 278(29):26929–26937

    Article  PubMed  CAS  Google Scholar 

  234. Gutierrez S, Mukdsi JH, Aoki A, Torres AI, Soler AP, Orgnero EM (2007) Ultrastructural immunolocalization of IGF-1 and insulin receptors in rat pituitary culture: evidence of a functional interaction between gonadotroph and lactotroph cells. Cell Tissue Res 327(1):121–132. doi:10.1007/s00441-006-0283-4

    Article  PubMed  CAS  Google Scholar 

  235. Yu SW, Baek SH, Brennan RT, Bradley CJ, Park SK, Lee YS, Jun EJ, Lookingland KJ, Kim EK, Lee H, Goudreau JL, Kim SW (2008) Autophagic death of adult hippocampal neural stem cells following insulin withdrawal. Stem Cells 26(10):2602–2610. doi:10.1634/stemcells.2008-0153

    Article  PubMed  CAS  Google Scholar 

  236. Yang JW, Raizada MK, Fellows RE (1981) Effects of insulin on cultured rat brain cells: stimulation of ornithine decarboxylase activity. J Neurochem 36(3):1050–1057

    Article  PubMed  CAS  Google Scholar 

  237. Wozniak M, Rydzewski B, Baker SP, Raizada MK (1993) The cellular and physiological actions of insulin in the central nervous system. Neurochem Int 22(1):1–10

    Article  PubMed  CAS  Google Scholar 

  238. Schechter R, Abboud M (2001) Neuronal synthesized insulin roles on neural differentiation within fetal rat neuron cell cultures. Dev Brain Res 127(1):41–49

    Article  CAS  Google Scholar 

  239. Xue ZG, Le Douarin NM, Smith J (1988) Insulin and insulin-like growth factor-I can trigger the differentiation of catecholaminergic precursors in cultures of dorsal root ganglia. Cell Differ Dev 25(1):1–10

    Article  PubMed  CAS  Google Scholar 

  240. Aizenman Y, Weichsel ME Jr, de Vellis J (1986) Changes in insulin and transferrin requirements of pure brain neuronal cultures during embryonic development. Proc Natl Acad Sci U S A 83(7):2263–2266

    Article  PubMed  CAS  Google Scholar 

  241. Léopold P (2004) Neuronal differentiation: TOR and insulin receptor pathways set the tempo. Cell 119(1):4–5

    Article  PubMed  Google Scholar 

  242. Recio-Pinto E, Lang FF, Ishii DN (1984) Insulin and insulin-like growth factor II permit nerve growth factor binding and the neurite formation response in cultured human neuroblastoma cells. Proc Natl Acad Sci U S A 81(8):2562–2566

    Article  PubMed  CAS  Google Scholar 

  243. Recio-Pinto E, Rechler MM, Ishii D (1986) Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci 6(5):1211–1219

    PubMed  CAS  Google Scholar 

  244. Ang LC, Bhaumick B, Juurlink BH (1993) Neurite promoting activity of insulin, insulin-like growth factor I and nerve growth factor on spinal motoneurons is astrocyte dependent. Brain Res Dev Brain Res 74(1):83–88

    Article  PubMed  CAS  Google Scholar 

  245. Heni M, Hennige AM, Peter A, Siegel-Axel D, Ordelheide AM, Krebs N, Machicao F, Fritsche A, Haring HU, Staiger H (2011) Insulin promotes glycogen storage and cell proliferation in primary human astrocytes. PLoS One 6(6):e21594. doi:10.1371/journal.pone.0021594

    Article  PubMed  CAS  Google Scholar 

  246. Schechter R, Yanovitch T, Abboud M, Johnson G III, Gaskins J (1998) Effects of brain endogenous insulin on neurofilament and MAPK in fetal rat neuron cell cultures. Brain Res 808(2):270–278

    Article  PubMed  CAS  Google Scholar 

  247. Schechter R, Abboud M, Johnson G (1999) Brain endogenous insulin effects on neurite growth within fetal rat neuron cell cultures. Brain Res Dev Brain Res 116(2):159–167

    Article  PubMed  CAS  Google Scholar 

  248. Vanhems E, Delbos M, Girardie J (1990) Insulin and neuroparsin promote neurite outgrowth in cultured locust CNS. Eur J Neurosci 2(9):776–782

    Article  PubMed  Google Scholar 

  249. Song J, Wu L, Chen Z, Kohanski RA, Pick L (2003) Axons guided by insulin receptor in Drosophila visual system. Science 300(5618):502–505. doi:10.1126/science.1081203

    Article  PubMed  CAS  Google Scholar 

  250. Recio-Pinto E, Ishii DN (1984) Effects of insulin, insulin-like growth factor-II and nerve growth factor on neurite outgrowth in cultured human neuroblastoma cells. Brain Res 302(2):323–334

    Article  PubMed  CAS  Google Scholar 

  251. Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, Murase T, Yoshikawa H (2011) Akt/mammalian target of rapamycin signaling pathway regulates neurite outgrowth in cerebellar granule neurons stimulated by methylcobalamin. Neurosci Lett 495(3):201–204. doi:10.1016/j.neulet.2011.03.065

    Article  PubMed  CAS  Google Scholar 

  252. Mill JF, Chao MV, Ishii DN (1985) Insulin, insulin-like growth factor II, and nerve growth factor effects on tubulin mRNA levels and neurite formation. Proc Natl Acad Sci U S A 82(20):7126–7130

    Article  PubMed  CAS  Google Scholar 

  253. Fernyhough P, Mill JF, Roberts JL, Ishii DN (1989) Stabilization of tubulin mRNAs by insulin and insulin-like growth factor I during neurite formation. Brain Res Mol Brain Res 6(2–3):109–120

    Article  PubMed  CAS  Google Scholar 

  254. Heidenreich KA, Toledo SP (1989) Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6. Endocrinology 125(3):1458–1463

    Article  PubMed  CAS  Google Scholar 

  255. Dufner A, Thomas G (1999) Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253(1):100–109

    Article  PubMed  CAS  Google Scholar 

  256. Garcia-Segura L, Barnea E, Biggers W, Naftolin F, Sanyal M (1986) Insulin modulates neuronal plasma membrane development in human fetal spinal cord neurons in culture. Neurosci Lett 65(3):283–286

    Article  PubMed  CAS  Google Scholar 

  257. Nemoto T, Yanagita T, Satoh S, Maruta T, Kanai T, Murakami M, Wada A (2011) Insulin-induced neurite-like process outgrowth: acceleration of tau protein synthesis via a phosphoinositide 3-kinase approximately mammalian target of rapamycin pathway. Neurochem Int 59(6):880–888. doi:10.1016/j.neuint.2011.08.002

    Article  PubMed  CAS  Google Scholar 

  258. Morita T, Sobue K (2009) Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem 284(40):27734–27745. doi:10.1074/jbc.M109.008177

    Article  PubMed  CAS  Google Scholar 

  259. Ryu BR, Ko HW, Jou I, Noh JS, Gwag BJ (1999) Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. J Neurobiol 39(4):536–546. doi:10.1002/(SICI)1097-4695(19990615)39:4<536::AID-NEU7>3.0.CO;2-J

    Article  PubMed  CAS  Google Scholar 

  260. Gunn-Moore FJ, Williams AG, Toms NJ, Tavare JM (1997) Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival. Biochem J 324(Pt 2):365–369

    PubMed  CAS  Google Scholar 

  261. Barber AJ, Nakamura M, Wolpert EB, Reiter CEN, Seigel GM, Antonetti DA, Gardner TW (2001) Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3. J Biol Chem 276(35):32814–32821

    Article  PubMed  CAS  Google Scholar 

  262. Yu XR, Jia GR, Gao GD, Wang SH, Han Y, Cao W (2006) Neuroprotection of insulin against oxidative stress-induced apoptosis in cultured retinal neurons: involvement of phosphoinositide 3-kinase/Akt signal pathway. Acta Biochim Biophys Sin (Shanghai) 38(4):241–248

    Article  CAS  Google Scholar 

  263. Moosavi M, Maghsoudi N, Zahedi-Asl S, Naghdi N, Yousefpour M, Trounce IA (2008) The role of PI3/Akt pathway in the protective effect of insulin against corticosterone cell death induction in hippocampal cell culture. Neuroendocrinology 88(4):293–298

    Article  PubMed  CAS  Google Scholar 

  264. Hamabe W, Fujita R, Ueda H (2005) Insulin receptor-protein kinase C-gamma signaling mediates inhibition of hypoxia-induced necrosis of cortical neurons. J Pharmacol Exp Ther 313(3):1027–1034. doi:10.1124/jpet.104.082735

    Article  PubMed  CAS  Google Scholar 

  265. Schafer M, Erdo SL (1992) Insulin-specific sensitization of cultured cerebrocortical neurons to glutamate excitotoxicity. Brain Res 580(1–2):331–333

    Article  PubMed  CAS  Google Scholar 

  266. Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 1783(6):994–1002. doi:10.1016/j.bbamcr.2008.02.016

    Article  PubMed  CAS  Google Scholar 

  267. Duarte AI, Santos MS, Oliveira CR, Rego AC (2005) Insulin neuroprotection against oxidative stress in cortical neurons—involvement of uric acid and glutathione antioxidant defenses. Free Radic Biol Med 39(7):876–889

    Article  PubMed  CAS  Google Scholar 

  268. Shindler KS, Yunker AM, Cahn R, Zha J, Korsmeyer SJ, Roth KA (1998) Trophic support promotes survival of bcl-x-deficient telencephalic cells in vitro. Cell Death Differ 5(10):901–910. doi:10.1038/sj.cdd.4400421

    Article  PubMed  CAS  Google Scholar 

  269. Jafari Anarkooli I, Sankian M, Vahedi F, Bonakdaran S, Varasteh AR, Haghir H (2009) Evaluation of insulin and ascorbic acid effects on expression of Bcl-2 family proteins and caspase-3 activity in hippocampus of STZ-induced diabetic rats. Cell Mol Neurobiol 29(1):133–140. doi:10.1007/s10571-008-9305-y

    Article  PubMed  CAS  Google Scholar 

  270. Wu X, Reiter CEN, Antonetti DA, Kimball SR, Jefferson LS, Gardner TW (2004) Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. J Biol Chem 279(10):9167–9175

    Article  PubMed  CAS  Google Scholar 

  271. Tanaka M, Sawada M, Yoshida S, Hanaoka F, Marunouchi T (1995) Insulin prevents apoptosis of external granular layer neurons in rat cerebellar slice cultures. Neurosci Lett 199(1):37–40

    Article  PubMed  CAS  Google Scholar 

  272. Li ZG, Zhang W, Grunberger G, Sima AA (2002) Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946(2):221–231

    Article  PubMed  CAS  Google Scholar 

  273. Zhuravliova E, Barbakadze T, Narmania N, Sepashvili M, Mikeladze D (2009) Hypoinsulinemia alleviates the Grf1/Ras/Akt anti-apoptotic pathway and induces alterations of mitochondrial ras trafficking in neuronal cells. Neurochem Res 34(6):1076–1082

    Article  PubMed  CAS  Google Scholar 

  274. Baek SH, Kim EK, Goudreau JL, Lookingland KJ, Kim SW, Yu SW (2009) Insulin withdrawal-induced cell death in adult hippocampal neural stem cells as a model of autophagic cell death. Autophagy 5(2):277–279

    Article  PubMed  CAS  Google Scholar 

  275. Li JW, Li LL, Chang LL, Wang ZY, Xu Y (2009) Stem cell factor protects against neuronal apoptosis by activating AKT/ERK in diabetic mice. Brazilian J Med Biol Res 42(11):1044–1049

    Article  CAS  Google Scholar 

  276. Molodtsov V, Senchenkov E, Bazhanova E (2006) Apoptosis and expression of vasopressin, insulin, and Bcl-2 in the neurosecretory system of aged mice. J Evol Biochem Physiol 42(3):354–360

    Article  CAS  Google Scholar 

  277. Okouchi M, Okayama N, Steven Alexander J, Yee Aw T (2006) NRF2-dependent glutamate-l-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia-induced brain endothelial cell apoptosis. Curr Neurovasc Res 3(4):249–261

    Article  PubMed  CAS  Google Scholar 

  278. Estevez AG, Radi R, Barbeito L, Shin JT, Thompson JA, Beckman JS (1995) Peroxynitrite-induced cytotoxicity in PC12 cells: evidence for an apoptotic mechanism differentially modulated by neurotrophic factors. J Neurochem 65(4):1543–1550

    Article  PubMed  CAS  Google Scholar 

  279. Mora A, Gonzalez-Polo RA, Fuentes JM, Soler G, Centeno F (1999) Different mechanisms of protection against apoptosis by valproate and Li+. Eur J Biochem 266(3):886–891

    Article  PubMed  CAS  Google Scholar 

  280. Duarte AI, Santos MS, Seica R, de Oliveira CR (2003) Insulin affects synaptosomal GABA and glutamate transport under oxidative stress conditions. Brain Res 977(1):23–30

    Article  PubMed  CAS  Google Scholar 

  281. Duarte AI, Santos MS, Seica R, Oliveira CR (2004) Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin. Diabetes 53(8):2110–2116

    Article  PubMed  CAS  Google Scholar 

  282. Butterfield DA, Castegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death. Neurobiol Aging 23(5):655–664

    Article  PubMed  Google Scholar 

  283. Garg R, Chaudhuri A, Munschauer F, Dandona P (2006) Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke 37(1):267–273. doi:10.1161/01.STR.0000195175.29487.30

    Article  PubMed  CAS  Google Scholar 

  284. Duarte AI, Proenca T, Oliveira CR, Santos MS, Rego AC (2006) Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. Diabetes 55(10):2863–2870. doi:10.2337/db06-0030

    Article  PubMed  CAS  Google Scholar 

  285. Sevanian A, Davies K, Hochstein P (1991) Serum urate as an antioxidant for ascorbic acid. Am J Clin Nutr 54(6):1129S

    PubMed  CAS  Google Scholar 

  286. Rensink AA, Otte-Holler I, de Boer R, Bosch RR, ten Donkelaar HJ, de Waal RM, Verbeek MM, Kremer B (2004) Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes. Neurobiol Aging 25(1):93–103

    Article  PubMed  CAS  Google Scholar 

  287. Di Carlo M, Picone P, Carrotta R, Giacomazza D, San Biagio PL (2010) Insulin promotes survival of amyloid-beta oligomers neuroblastoma damaged cells via caspase 9 inhibition and Hsp70 upregulation. J Biomed Biotechnol 2010:147835. doi:10.1155/2010/147835

    PubMed  Google Scholar 

  288. Takadera T, Sakura N, Mohri T, Hashimoto T (1993) Toxic effect of a beta-amyloid peptide (beta 22–35) on the hippocampal neuron and its prevention. Neurosci Lett 161(1):41–44

    Article  PubMed  CAS  Google Scholar 

  289. Voll CL, Auer RN (1991) Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab 11(6):1006–1014. doi:10.1038/jcbfm.1991.168

    Article  PubMed  CAS  Google Scholar 

  290. Zhu CZ, Auer RN (1994) Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia. J Cereb Blood Flow Metab 14(2):237–242. doi:10.1038/jcbfm.1994.30

    Article  PubMed  CAS  Google Scholar 

  291. Sun X, Yao H, Douglas RM, Gu XQ, Wang J, Haddad GG (2010) Insulin/PI3K signaling protects dentate neurons from oxygen-glucose deprivation in organotypic slice cultures. J Neurochem 112(2):377–388. doi:10.1111/j.1471-4159.2009.06450.x

    Article  PubMed  CAS  Google Scholar 

  292. Cheng B, Mattson MP (1992) IGF-I and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycemic damage. J Neurosci 12(4):1558–1566

    PubMed  CAS  Google Scholar 

  293. Rizk NN, Rafols JA, Dunbar JC (2006) Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide. Brain Res 1096(1):204–212. doi:10.1016/j.brainres.2006.04.060

    Article  PubMed  CAS  Google Scholar 

  294. Auer RN (1998) Insulin, blood glucose levels, and ischemic brain damage. Neurology 51(3 Suppl 3):S39–S43

    Article  PubMed  CAS  Google Scholar 

  295. Shuaib A, Ijaz MS, Waqar T, Voll C, Kanthan R, Miyashita H, Liu L (1995) Insulin elevates hippocampal GABA levels during ischemia. This is independent of its hypoglycemic effect. Neuroscience 67(4):809–814

    Article  PubMed  CAS  Google Scholar 

  296. Grunstein HS, James DE, Storlien LH, Smythe GA, Kraegen EW (1985) Hyperinsulinemia suppresses glucose utilization in specific brain regions: in vivo studies using the euglycemic clamp in the rat. Endocrinology 116(2):604–610

    Article  PubMed  CAS  Google Scholar 

  297. Hui L, Pei DS, Zhang QG, Guan QH, Zhang GY (2005) The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation. Brain Res 1052(1):1–9. doi:10.1016/j.brainres.2005.05.043

    Article  PubMed  CAS  Google Scholar 

  298. Collino M, Aragno M, Castiglia S, Tomasinelli C, Thiemermann C, Boccuzzi G, Fantozzi R (2009) Insulin reduces cerebral ischemia/reperfusion injury in the hippocampus of diabetic rats: a role for glycogen synthase kinase-3beta. Diabetes 58(1):235–242. doi:10.2337/db08-0691

    Article  PubMed  CAS  Google Scholar 

  299. Tang F, Yan C, Li F, Wu S, Yu Y, Gao Y, Jin X, Tian Y, Shen X (2007) Protective effects of insulin on polychlorinated biphenyls-induced disruption of actin cytoskeleton in hippocampal neurons. Environ Toxicol 22(2):152–158. doi:10.1002/tox.20247

    Article  PubMed  CAS  Google Scholar 

  300. Ang LC, Bhaumick B, Munoz DG, Sass J, Juurlink BH (1992) Effects of astrocytes, insulin and insulin-like growth factor I on the survival of motoneurons in vitro. J Neurol Sci 109(2):168–172

    Article  PubMed  CAS  Google Scholar 

  301. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38. doi:10.1001/archneurol.2011.233

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to the Neuroscience Research Center; Shahid Beheshti University of Medical Sciences; and Department of Pharmacology, Faculty of Medicine, University of Malaya for support of this work, in collaboration.

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The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Rasoul Ghasemi

  2. Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Ali Haeri

  3. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Leila Dargahi

  4. Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia

    Zahurin Mohamed & Abolhassan Ahmadiani

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  1. Rasoul Ghasemi
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Correspondence to Abolhassan Ahmadiani.

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Ghasemi, R., Haeri, A., Dargahi, L. et al. Insulin in the Brain: Sources, Localization and Functions. Mol Neurobiol 47, 145–171 (2013). https://doi.org/10.1007/s12035-012-8339-9

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