Insulin, Hypoglycemia, and Ischemic Neuroprotection

  • Roland N. Auer
Part of the Advances in Neuroprotection book series (volume 22)


Hypoglycemia, if profound, may give rise to cerebral EEG isoelectricity [blood glucose levels < 1.4 mM, but usually < 1 mM in controlled experimental studies (Auer et al., 1984a)]. EEG silence is the harbinger of a series of biochemical events leading to hypoglycemic brain damage (Siesjö, 1988), structurally manifest as neuronal death (Auer et al., 1984b). Since hypoglycemia is one of the major effects of insulin administration, the very suggestion of the use of insulin in the possible treatment of cerebral ischemia may understandably be viewed with initial skepticism.


Brain Damage Insulin Administration Cereb Blood Flow Spinal Cord Ischemia Ischemic Brain Damage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albrecht J, Wróblewska B, Mossakowski M (1982): The binding of insulin to cerebral capillaries and astrocytes of the rat. Neurochem Res 7: 489–494CrossRefGoogle Scholar
  2. Araujo DM, Lapchak PA, Collier B, Chabot J-G, Quirion R (1989): Insulin-like growth factor-1 (somatomedin-C) receptors in the rat brain: Distribution and interaction with the hippocampal cholinergic system. Brain Res 484: 130–138CrossRefGoogle Scholar
  3. Auer RN, Olsson Y, Siesjö BK (1984a): Hypoglycemic brain injury in the rat: Correlation of density of brain damage with the EEG isoelectric time: A quantitative study. Diabetes 33: 1090–1098CrossRefGoogle Scholar
  4. Auer RN, Wieloch T, Olsson Y, Siesjö BK (1984b): The distribution of hypoglycemic brain damage. Acta Neuropathol (Berl) 64: 177–191CrossRefGoogle Scholar
  5. Auer RN, Hall P, Ingvar M, Siesjö BK (1986): Hypotension as a complication of hypoglycemia leads to enhanced energy failure but no increase in neuronal necrosis. Stroke 17: 442–449CrossRefGoogle Scholar
  6. Auer RN (1986): Hypoglycemic brain damage. Stroke 17: 488–496CrossRefGoogle Scholar
  7. Blomqvist P, Lindvall O, Wieloch T (1985): Lesions of the locus coeruleus system aggravate ischemic damage in the rat brain. Neurosci Lett 58: 353–358CrossRefGoogle Scholar
  8. Bouhaddi K, Thomopoulos P, Fages C, Khelil M, Tardy M (1988): Insulin effect on GABA uptake in astroglial primary cultures. Neurochem Res 13: 1119–1124CrossRefGoogle Scholar
  9. Calhoun CL, Mottaz JH (1966): Capillary bed of the rat cerebral cortex: The fine structure in experimental cerebral infarction. Arch Neurol 15: 320–328CrossRefGoogle Scholar
  10. Carpenter DO, Briggs DB (1986): Insulin excites neurons of the area postrema and causes emesis. Neurosci Lett 68: 85–89CrossRefGoogle Scholar
  11. Duffy KR, Pardridge WM (1987): Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 420: 32–38CrossRefGoogle Scholar
  12. Frank HJL, Pardridge WM (1981): A direct in vitro demonstration of insulin binding to isolated brain microvessels. Diabetes 30: 757–761CrossRefGoogle Scholar
  13. Fukuoka S, Yeh H-S, Mandybur TI, Tew JM Jr (1989): Effect of insulin on acute experimental cerebral ischemia in gerbils. Stroke 20: 396–399CrossRefGoogle Scholar
  14. Gjedde A, Hansen AJ, Siemkowicz E (1980): Rapid simultaneous determination of regional blood flow and blood-brain glucose transfer in brain of rat. Acta Physiol Scand 108: 321–330CrossRefGoogle Scholar
  15. 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: 604–610CrossRefGoogle Scholar
  16. Hill JM, Lesniak MA, Pert CB, Roth J (1986): Autoradiographic localization of insulin receptors in rat brain: Prominence in olfactory and limbic areas. Neuroscience 17: 1127–1138CrossRefGoogle Scholar
  17. Hill JM, Lesniak MA, Pert CB (1988): Co-localization of IGF-II receptors, IL-1 receptors and thy 1.1 in rat brain. Peptides 9 (Suppl 1):91–96Google Scholar
  18. Ito U, Spatz M, Walker JT Jr, Klatzo I (1975): Experimental cerebral ischemia in Mongolian gerbils. I. Light microscopic observations. Acta Neuropathol (Berl) 32: 209–223CrossRefGoogle Scholar
  19. Kirino T (1982): Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239: 57–69CrossRefGoogle Scholar
  20. Kirino T, Tamura A, Tomukai N, Sano K (1986): Treatable ischemic neuronal damage in the gerbil hippocampus. No To Shinkei 38: 1157–1163Google Scholar
  21. Koide T, Wieloch TW, Siesjö BK (1986): Circulating catecholamines modulate ischemic brain damage. J Cereb Blood Flow Metab 6: 559–565CrossRefGoogle Scholar
  22. Kraig RP, Petito CK, Plum F, Pulsinelli WA (1987): Hydrogen ions kill brain at concentrations reached in ischemia. J Cereb Blood Flow Metabol 7: 379–386CrossRefGoogle Scholar
  23. Kraig RP, Chesler M (1990): Astrocytic acidosis in hyperglycemic and complete ischemia. J Cerebr Blood Flow Metab 10: 104–114CrossRefGoogle Scholar
  24. Krumholz A, Stern BJ, Weiss HD (1988): Outcome from coma after cardiopulmo- nary resuscitation: Relation to seizures and myoclonus. Neurology 38: 401–405CrossRefGoogle Scholar
  25. LeMay DR, Gehua L, Zelenock GB, D’Alecy G (1988a): Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke 19: 1411–1419CrossRefGoogle Scholar
  26. LeMay DR, Lu AC, Zelenock GB, D’Alecy LG (1988b): Insulin administration protects from paraplegia in the rat aortic occlusion model. J Surg Res 44: 352–358CrossRefGoogle Scholar
  27. Longstreth W Jr, Inui TS (1984): High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest. Ann Neurol 15: 59–63CrossRefGoogle Scholar
  28. Longstreth WT Jr, Diehr P, Cobb LA, Hanson RW, Blair AD (1986): Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation. Neurology 36: 1186–1191CrossRefGoogle Scholar
  29. Lucignani G, Namba H, Nehlig A, Porrino LJ, Kennedy C, Sokoloff L (1987): Effects of insulin on local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab 7: 309–314CrossRefGoogle Scholar
  30. Margolis R, Altszuler N (1967): Insulin in the cerebrospinal fluid. Nature 215: 1375–1376CrossRefGoogle Scholar
  31. 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: 247–256CrossRefGoogle Scholar
  32. McCaleb M, Myers RD, Singer G, Willis G (1979): Hypothalamic norepinephrine in the rat during feeding and push-pull perfusion with glucose, 2-DG, or insulin. Am J Physiol 236: R312–321Google Scholar
  33. Meyer JS, Portnoy HD (1958): Localized cerebral hypoglycemia simulating stroke. Neurology 8: 601–614CrossRefGoogle Scholar
  34. Myers RE (1979): Lactic acid accumulation as a cause of brain edema and cerebral necrosis resulting from oxygen deprivation. Advan Perinatal Neurol pp 85–114Google Scholar
  35. Myers RE, Yamaguchi S (1977): Nervous system effects of cardiac arrest in monkeys. Arch Neurol 34: 65–74CrossRefGoogle Scholar
  36. Palovcik RA, Phillips MI, Kappy MS, Raizada MK (1984): Insulin inhibits pyramidal neurons in hippocampal slices. Brain Res 309: 187–191CrossRefGoogle Scholar
  37. Rehncrona S, Rosén I, Siesjö BK (1981): Brain lactic acidosis and ischemic cell damage. I. Biochemistry and neurophysiology. J Cereb Blood Flow Metab 1: 297–311CrossRefGoogle Scholar
  38. Robertson CS, Grossman RG (1987): Protection against spinal cord ischemia with insulin-induced hypoglycemia. J Neurosurg 67: 739–744CrossRefGoogle Scholar
  39. Rothman SM, Olney JW (1986): Glutamate and the pathophysiology of hypoxic/ ischemic brain damage. Ann Neurol 19: 105–111CrossRefGoogle Scholar
  40. Salter CF, Chiodo LA (1980): Glucose suppresses basal firing and haloperidolinduced increases in the firing rate of central dopaminergic neurons. Science 210: 1269–1271CrossRefGoogle Scholar
  41. Shiu RPC, Paterson JA (1988): Characterization of insulin-like growth factor II peptides secreted by explants of neonatal brain and of adult pituitary from rats. Endocrinology 123: 1456–1460CrossRefGoogle Scholar
  42. Siemkowicz E, Hansen AJ, Gjedde A (1982): Hyperglycemic ischemia of rat brain: The effect of post-ischemic insulin on metabolic rate. Brain Res 243: 386–390CrossRefGoogle Scholar
  43. Siesjö BK, Ingvar M, Pelligrino D (1983): Regional differences in vascular auto-regulation in the rat brain in severe insulin-induced hypoglycemia. J Cereb Blood Flow Metab 3: 478–485CrossRefGoogle Scholar
  44. Siesjö BK (1988): Hypoglycemia, brain metabolism, and brain damage. Diabetes/ Metab Rev 4: 113–141CrossRefGoogle Scholar
  45. Stahl W (1986): The Na,K-ATPase of nervous tissue. Neurochem Int 8:449–476CrossRefGoogle Scholar
  46. Sternau LL, Lust WD, Ricci AJ, Ratcheson R (1989): Role for -y-aminobutyric acid in selective vulnerability in gerbils. Stroke 20: 281–287CrossRefGoogle Scholar
  47. Strong Ai, Miller SA, West IC (1985): Protection of respiration of a crude mitochondrial preparation in cerebral ischaemia by control of blood glucose. J Neurol Neurosurg Psychiatry 48: 450–454CrossRefGoogle Scholar
  48. Strong AJ, Fairfield JE, Monteiro E, Kirby M, Hogg AR, Snape M, Ross-Field L (1990): Insulin protects cognitive function in experimental stroke. J Neurol Neurosurg Psychiatry 53: 847–853CrossRefGoogle Scholar
  49. Voll CL, Auer RN (1988): The effect of post-ischemic blood glucose levels on the density and distribution of ischemic brain damage in the rat. Ann Neurol 24: 638–646CrossRefGoogle Scholar
  50. Voll CL, Whishaw IQ, Auer RN (1989): Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in the rat. Stroke 20: 646–651CrossRefGoogle Scholar
  51. Voll CL, Auer RN (1991a): Postischemic seizures and necrotizing ischemic brain damage: Neuroprotective effect of postischemic diazepam and insulin. Neurology 41: 423–428CrossRefGoogle Scholar
  52. Voll CL, Auer RN (1991b): Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cerebr Blood Flow Metab 11: 1006–1014CrossRefGoogle Scholar
  53. Wallum BJ, Taborsky GJ Jr, Porte D Jr, Figlewicz DP, Jacobson L, Beard JC, Ward WK, Dorsa D (1987): Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 64: 190–194CrossRefGoogle Scholar
  54. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Allen AM, Mendelsohn FAO (1987): Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121: 1562–1570CrossRefGoogle Scholar
  55. Whishaw IQ (1985): Formation of a place learning-set in the rat: A new procedure for neurobehavioral studies. Physiol Behav 35: 139–143CrossRefGoogle Scholar
  56. Young GB, Gilbert JJ, Zochodne DW (1990): The significance of myoclonic status epilepticus in postanoxic coma. Neurology 40: 1843–1848CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1992

Authors and Affiliations

  • Roland N. Auer

There are no affiliations available

Personalised recommendations