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Vol. 74, No. 4, 2001
Issue release date: October 2001

Improving Influence of Insulin on Cognitive Functions in Humans

Kern W. · Peters A. · Fruehwald-Schultes B. · Deininger E. · Born J. · Fehm H.L.
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Abstract

Insulin receptors have been identified in limbic brain structures, but their functional relevance is still unclear. In order to characterize some of their effects, we evaluated auditory evoked brain potentials (AEP) in a vigilance task, behavioral measures of memory (recall of words) and selective attention (Stroop test) during infusion of insulin. The hormone was infused at two different rates (1.5 mU/kg × min, ‘low insulin’, and 15 mU/kg × min, ‘high insulin’), inducing respectively serum levels of 543 ± 34 and 24,029 ± 1,595 pmol/l. This experimental design allowed to compare cognitive parameters under two conditions presenting markedly different insulin levels, but with minimal incidence on blood glucose concentrations since these were kept constant by glucose infusion. A ‘no insulin treatment’ group was not included in order to avoid leaving patients infused with glucose without insulin treatment. Measures were taken during a baseline phase preceding insulin infusion and every 90 min during the 360 min of insulin infusion. Compared with ‘low insulin’, ‘high insulin’ induced a slow negative potential shift in the AEP over the frontal cortex (average amplitude, high insulin: 0.27 ± 0.48 µV; low insulin: 1.87 ± 0.48 µV, p < 0.005), which was paralleled by enhanced memory performance (words recalled, high insulin: 22.04 ± 0.93; low insulin: 19.29 ± 0.92, p < 0.05). Also, during ‘high insulin’ subjects displayed enhanced performance on the Stroop test (p < 0.05) and expressed less difficulty in thinking than during ‘low insulin’ (p < 0.03). Results indicate an improving effect of insulin on cognitive function, and may provide a frame for further investigations of neurobehavioral effects of insulin in patients with lowered or enhanced brain insulin, i.e., patients with Alzheimer’s disease or diabetes mellitus.



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References

  1. Baskin DG, Figlewicz DP, Woods SC, Porte D Jr, Dorsa DM: Insulin in the brain. Annu Rev Psychol 1987;49:334–347.
  2. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC, Porte D Jr: Insulin in the brain: A hormonal regulator of energy balance. Endocr Rev 1992;13:387–413.
  3. Poduslo JF, Curran GL, Berg CT: Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc Natl Acad Sci USA 1997;91:5705–5709.
  4. Unger JW, Livingston JN, Moss AM: Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects. Prog Neurobiol 1991;36:343–362.
  5. Kessler JA, Spray DC, Saez JC, Bennett MVL: Determination of synaptic phenotype: Insulin and cAMP independently initiate development of electrotonic coupling between cultured sympathetic neurons. Proc Natl Acad Sci USA 1984;81:6235–6239.
  6. Palovcik RA, Philiphs MI, Kappy MS, Raizada MK: Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res 1984;309:187–191.
  7. Shibata S, Liou SY, Ueki S, Oomura Y: Inhibitory action of insulin on suprachiasmatic nucleus neurons in rat hypothalamic slice preparation. Physiol Behav 1985;36:79–81.
  8. Sakaguchi T, Bray GA: Intrahypothalamic injection of insulin decreases firing rate of sympathetic nerves. Proc Natl Acad Sci USA 1987;84:2012–2014.
  9. Masters BA, Shemer J, Judkins JH, Clarke DW, LeRoith D, Raizada MK: Insulin receptors and insulin action in dissociated brain cells. Brain Res 1987;417:247–256.
  10. Peinado JM, Meyers RD: Norepinephrine release from PVN and lateral hypothalamus during perfusion with 2-DG or insulin in the seated and fasted rat. Pharmacol Biochem Behav 1991;27:715–721.
  11. Figlewicz DP, Szot P: Insulin stimulates membrane phospholipid metabolism by enhancing endogenous alpha-1-adrenergic activity in the rat hippocampus. Brain Res 1991;550:101–107.
  12. Duelli R, Schrock H, Kuschinsky W, Hoyer S: Intracerebroventricular injection of steptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994;12:737–743.
  13. Plaschke K, Hoyer S: Action of the diabetogenic drug streptozotocin on glycolytic metabolism in adult brain and hippocampus. Int J Dev Neurosci 1993;11:477–483.
  14. Henneberg N, Hoyer S: Short-term or long-term intracerebroventricular infusion of insulin exhibits a discrete anabolic effect on cerebral energy metabolism in the rat. Neurosci Lett 1994;175:153–156.
  15. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr: Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease. Neurology 1998;50:164–168.
  16. McCall AL: The impact of diabetes on the CNS. Diabetes 1992;41:557–570.
  17. Strachan MWJ, Deary IJ, Ewing FME, Frier BM: Is type II diabetes associated with an increased risk of cognitive dysfunction? Diabetes Care 1997;20:438–445.
  18. Pozzessere G, Valle E, De Crignis S, Cordischi VM, Fattapposta F, Rizzo PA, Pietravalle P, Cristina G, Morano S, Di Mairo U: Abnormalities of cognitive functions in IDDM revealed by P300 event-related potential analysis. Diabetes 1991;40:952–958.
  19. Kurita A, Katayama K, Mochio S: Neurophysiological evidence for altered higher brain functions in NIDDM. Diabetes Care 1996;19:361–364.
  20. The Diabetes Control and Complications Trial Research Group: Hypoglycemia in the Diabetes Control and Complication Trial. Diabetes 1997;46:271–286.
  21. Wickelgren I: Tracking insulin to the mind. Science 1998;280:517–519.
  22. Wallace WC, Akar CA, Lyons WE, Kole HK, Egan JM, Wolozin B: Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity. Brain Res Mol Brain Res 1997;52:213–227.

    External Resources

  23. Izumi Y, Pinard E, Roussel S, Seylaz J: Insulin protects brain tissue against focal ischemia in rats. Neurosci Lett 1992;144:121–123.
  24. Voll CL, Whishaw IQ, Auer RN: Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989;20:646–651.

    External Resources

  25. Kern W, Born J, Schreiber H, Fehm HL: Central nervous system effects of intranasally administered insulin during euglycemia in humans. Diabetes 1999;48:557–563.
  26. Näätänen R, Picton TW: The N1 wave of the human electric and magnetic response to sound: A review and an analysis of the component structure. Psychophysiology 1987;24:375–425.
  27. Donchin E: Surprise ... surprise? Psychophysiology 1981;18:493–513.

    External Resources

  28. Golden C: Stroop Color and Word Test. Chicago, Stoelting, 1978.
  29. Bergendahl M, Vance ML, Iranmanesh A, Thorner MO, Veldhuis JD: Fasting as a metabolic stress paradigm selectively amplifies cortisol secretory burst mass and delays the time of maximal nyctohemeral cortisol concentrations in healthy men. J Clin Endocrinol Metab 1996;81:692–699.
  30. Sakaguchi T, Arase K, Fisler JS, Bray GA: Effect of starvation and food intake on sympathetic activity. Am J Physiol 1988;255:R284–R288.

    External Resources

  31. Schwartz MW, Seeley RJ: Neuroendocrine responses to starvation and weight loss. N Engl J Med 1997;336:1802–1811.
  32. Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF: Responses of leptin to short-term fasting and refeeding in humans. A link with ketogenesis but not ketones themselves. Diabetes 1996;45:1511–1515.
  33. Kern W, Offenheuser S, Born J, Fehm HL: Entrainment of ultradian oscillations in the secretion of insulin and glucagon to the non-REM/REM sleep rhythm in humans. J Clin Endocrinol Metab 1996;81:1541–1547.

    External Resources

  34. Baron AD: Hemodynamic actions of insulin. Am J Physiol 1994;267:E187–E202.
  35. Kolterman OG, Insel J, Saekow M, Olefsky JM: Mechanisms of insulin resistance in human obesity. J Clin Invest 1980;65:1272–1284.

    External Resources

  36. Lingenfelser T, Overkamp D, Renn W, Buettner U, Kimmerle K, Schmalfuss A, Jakober B: Insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus: Evidence for an intrinsic effect of insulin on the central nervous system. J Clin Endocrinol Metab 1996;81:1197–1205.
  37. Schwartz MW, Sipols AJ, Kahn SE, Lattemann DP, Taborsky GJ Jr, Bergman RN, Woods SC, Porte D Jr: Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol 1990;259:E378–E383.

    External Resources

  38. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW: Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. J Clin Invest 1993;92:1824–1830.
  39. Rockstroh B, Elbert T, Canavan AGMT, Lutzenberger W, Birbaumer N: Slow Cortical Potentials. München, Urban & Schwarzenberg, 1989.
  40. Smid HGOM, Trümper BG, Pottag G, Wagner K, Lobmann R, Scheich HM, Lehnert H, Heinze HJ: Differentiation of hypoglycemia-induced cognitive impairments. Brain 1997;120:1041–1056.

    External Resources

  41. Lobmann R, Smid H, Pottag G, Wagner K, Heinze HJ, Lehnert H: Changes in information processing during a hypoglycemic clamp in type-II-diabetic patients. Exp Clin Endocrinol Diabetes 1998;106:S63.

    External Resources

  42. Ruchkin DS, Johnson R Jr, Mahaffey D, Sutton S: Towards a functional categorization of slow waves. Psychophysiology 1988;25:339–353.

    External Resources

  43. Birbaumer N, Roberts LE, Lutzenberger W, Rockstroh B, Elbert T: Area-specific self-regulation of slow cortical potentials on the sagittal midline and its effects on behaviour. Electroenceph Clin Neurophysiol 1992;84:353–361.
  44. Karis D, Fabiani M, Donchin E: ‘P300’ and memory: Individual differences in the von Restorff effect. Cogn Psychol 1984;16:177–216.
  45. Pelosi L, Hayward M, Blumhardt LD: Which event-related potentials reflect memory processing in a digit-probe identification task? Cogn Brain Res 1998;6:205–218.
  46. Mecklinger A, Kramer AF, Strayer DL: Event-related potentials and EEG components in a semantic memory search task. Psychophysiology 1992;29:104–119.
  47. Pelosi L, Holly M, Slade T, Hayward M, Barrett G, Blumhardt LD: Wave form variations in auditory event-related potentials evoked by a memory-scanning task and their relationship with tests of intellectual function. Electroenceph Clin Neurophysiol 1992;84:344–352.
  48. Lang W, Lang M, Podreka I, Steiner M, Uhl F, Suess E, Müller C, Deecke L: DC-potential shifts and regional blood flow reveal frontal cortex involvement in human visuomotor learning. Exp Brain Res 1988;71:353–364.

    External Resources

  49. Gerbrandt LK, Lawrence JC, Eckardt MJ, Lloyd RL: Origin of the neocortically monitored theta rhythm in the curarized rat. Electronenceph Clin Neurophysiol 1978;45:454–467.
  50. Shinba T, Andow Y, Shinozaki T, Ozawa N, Yamamoto K: Event-related potentials in the dorsal hippocampus of rats during an auditory discrimination task. Electroenceph Clin Neurophysiol 1996;100:563–568.
  51. Halgren E, Squires NK, Wilson CL, Rohrbaugh JW, Babb TL, Crandall PH: Endogenous potentials generated in the hippocampal formation and amygdala by infrequent events. Science 1980;210:803–805.
  52. Okada YC, Kaufman L, Williamson SJ: The hippocampal formation as a source of the slow endogenous potentials. Electroenceph Clin Neurophysiol 1983;55:417–426.
  53. Caudle RM: The demonstration of long latency potentials in the CA1 region of the rat hippocampal slice. Brain Res 1993;613:247–250.
  54. Tarkka IM, Stokic DS, Basile LF, Papanicolaou AC: Electric source localization of the auditory P300 agrees with magnetic source localization. Electroenceph Clin Neurophysiol 1995;96:538–545.
  55. Marfaing P, Pénicaud L, Broer Y, Mraovitch S, Calando Y, Picon L: Effect of hyperinsulinemia on local cerebral insulin binding and glucose utilization in normoglycemic awake rats. Neurosci Lett 1990;115:279.
  56. Squire LR: Memory and the hippocampus: A synthesis of findings with rats, monkeys, and humans. Psychol Rev 1992;99:195.
  57. Messier C, White NM: Memory improvement by glucose, fructose, and two glucose analogs: A possible effect on peripheral glucose transport. Behav Neural Biol 1987;48:104–127.
  58. Long JM, Davis BJ, Garofalo P, Spangler EL, Ingram DK: Complex maze performance in young and aged rats: Response to glucose treatment and relationship to blood insulin and glucose. Physiol Behav 1992;51:411–418.
  59. Mayer G, Nitsch R, Hoyer S: Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 1990;532:95–100.
  60. Santucci AC, Schroeder H, Riccio DC: Homeostatic disruption and memory: Effect of insulin administration in rats. Behav Neural Biol 1990;53:321–333.
  61. Flood JF, Mooradian Ad, Morley JE: Characteristics of learning and memory in streptozocin-induced diabetic mice. Diabetes 1990;39:1391–1398.
  62. Shiosaka S: Attempts to make models for Alzheimer’s disease. Neurosci Res 1992;13:237.
  63. Durkin TP, Messier C, De Boer P, Westerink BHC: Raised glucose levels enhance scopolamine-induced acetylcholine overflow from the hippocampus: An in vivo microdialysis study in the rat. Behav Brain Res 1992;49:181.
  64. Stone WS, Cotrill KL, Walker DL, Gold PE: Blood glucose and brain function: Interactions with CNS cholinergic systems. Behav Neural Biol 1988;50:325.

    External Resources

  65. Messier C, Destrade C: Insulin attenuates scopolamine-induced memory deficits. Psychobiology 1994;22:16–21.
  66. Nader K, Schafe GE, Le Doux JE: Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 2000;406:722–726.
  67. Boyd FT, Clarke DW, Muther TF, Raizada MK: Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain. J Biol Chem 1985;260:15880–15884.

    External Resources

  68. McEwen B: Glucocorticoid receptors in the brain. Hosp Pract 1988;23:107–121.
  69. Lezak MD: Neuropsychological Assessment. New York, Oxford University Press, 1993, pp 1–48.
  70. Taylor SF, Kornblum S, Lauber EJ, Minoshima S, Koeppe RA: Isolation of specific interference processing in the stroop task: PET activation studies. Neuroimage 1997;6:81–92.
  71. Okita T, Wijers AA, Mulder G, Mulder LJM: Memory search and visual spatial attention: An event-related brain potential analysis. Acta Psychol 1985;60:263–292.
  72. Näätänen R: Processing negativity: An evoked-potential reflection of selective attention. Psychol Bull 1982;92:605–640.
  73. Wallum BJ, Porte D Jr, Figlewicz DP, Jacobson L, Dorsa D: Cerebrospinal fluid insulin levels increase during intravenous insulin infusion in man. J Clin Endocrinol Metab 1987;64:190–194.
  74. Banks WA, Jaspan JB, Kastin AJ: Effect of diabetes mellitus on the permeability of the blood-brain barrier to insulin. Peptides 1997;18:1577–1584.

    External Resources

  75. Boyd FT, Raizada MK: Effects of insulin and tunicamycin on neuronal insulin receptors in culture. Am J Physiol 1983;245:C283–C287.

    External Resources

  76. Clarke DW, Boyd FT, Kappy MS, Raizada MK: Insulin stimulates macromolecular synthesis in cultured glial cells from brain. Am J Physiol 1985;249:C484–C489.

    External Resources

  77. Boyle PJ, Nagy RJ, O’Connor AM, Kempers SF, Yeo RA, Qualls C: Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci USA 1994;91:9352–9356.


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