Insulin reduction of cerebral infarction due to transient focal ischemia

Mark G. Hamilton M.D., F.R.C.S.C. 1 , Bruce I. Tranmer M.D., F.R.C.S.C. 1 and Roland N. Auer M.D., Ph.D., F.R.C.P.C. 1
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  • 1 Departments of Clinical Neurosciences and Pathology, Neuroscience Research Group, University of Calgary, Calgary, Alberta, Canada
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✓ Insulin has recently been shown to ameliorate damage in models of global brain ischemia. To determine whether insulin is also neuroprotective in focal ischemia, 20 rats were given 2 to 3 IU/kg insulin and 10 did not receive treatment prior to normothermic transient middle cerebral artery occlusion for 2 hours at a blood pressure of 60 mm Hg. To further elucidate whether infarction volume is influenced by variations in blood glucose levels within the physiological range, blood glucose was raised in 10 of the insulin-treated animals to levels comparable with the untreated controls. At 1-week survival, damage was assessed using quantitative neuropathological examination of 25 coronal planes. It was found that preischemic insulin lowered the mean intraischemic blood glucose level from 8.4 ± 0.2 mM (µ ± standard error of the mean) in the control group to 3.4 ± 0.2 mM and reduced total damage (atrophy plus cortical and striatal necrosis), expressed as the percentage of the normal hemisphere, from a control of 28.5% ± 2.9% to 14.5% ± 1.6% (p < 0.005). Coadministration of glucose and insulin resulted in a mean intraischemic blood glucose level of 10.1 ± 0.5 mM, with 27.0% ± 2.4% total damage (p = 0.96, compared with control). Total ischemic damage showed an independent correlation with blood glucose levels (r = 0.67, p = 0.0018).

The findings indicate that insulin benefits transient focal ischemia and that reducing the blood glucose from 8 to 9 mM to the low-normal range of 3 to 4 mM with insulin dramatically reduces subsequent infarction. The data suggest that the neuroprotective mechanism of insulin action in focal middle cerebral artery occlusion is mediated predominantly via alterations in blood glucose levels. In comparison to global ischemia, focal ischemia appears to show only a minor direct central nervous system effect of insulin. In clinical situations in which transient focal ischemia to the hemisphere can be anticipated, insulin-induced hypoglycemia of a mild degree may be beneficial.

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Contributor Notes

Address reprint requests to: Roland Auer, M.D., Ph.D., University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
  • 1.

    Auer RN, , Olsson Y, & Siesjö BK: Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 33:10901098, 1984 Auer RN, Olsson Y, Siesjö BK: Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 33:1090–1098, 1984

    • Search Google Scholar
    • Export Citation
  • 2.

    Bederson JB, , Pitts LH, & Tsuji M, et al: Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472476, 1986 Bederson JB, Pitts LH, Tsuji M, et al: Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476, 1986

    • Search Google Scholar
    • Export Citation
  • 3.

    Buchan AM, , Xue D, & Slivka A: A new model of temporary focal neocortical ischemia in the rat. Stroke 23:273279, 1992 Buchan AM, Xue D, Slivka A: A new model of temporary focal neocortical ischemia in the rat. Stroke 23:273–279, 1992

    • Search Google Scholar
    • Export Citation
  • 4.

    Candelise L, , Landi G, , Orazio EN, & Boccardi E: Prognostic significance of hypoglycemia in acute stroke. Arch Neurol 42:661663, 1985 Candelise L, Landi G, Orazio EN, Boccardi E: Prognostic significance of hypoglycemia in acute stroke. Arch Neurol 42:661–663, 1985

    • Search Google Scholar
    • Export Citation
  • 5.

    Chopp M, , Welch KMA, & Tidwell CD, et al: Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia in cats. Stroke 19:13831387, 1988 Chopp M, Welch KMA, Tidwell CD, et al: Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia in cats. Stroke 19:1383–1387, 1988

    • Search Google Scholar
    • Export Citation
  • 6.

    Cole DJ, , Drummond JC, & Ghazal EA, et al: A reversible component of cerebral injury as identified by the histochemical stain 2,3,5-triphenyltetrazolium chloride (TTC). Acta Neuropathol 80:152155, 1990 Cole DJ, Drummond JC, Ghazal EA, et al: A reversible component of cerebral injury as identified by the histochemical stain 2,3,5-triphenyltetrazolium chloride (TTC). Acta Neuropathol 80:152–155, 1990

    • Search Google Scholar
    • Export Citation
  • 7.

    Dávalos A, , Cendra E, & Teruel J, et al: Deteriorating ischemic stroke: risk factors and prognosis. Neurology 40:18651869, 1990 Dávalos A, Cendra E, Teruel J, et al: Deteriorating ischemic stroke: risk factors and prognosis. Neurology 40:1865–1869, 1990

    • Search Google Scholar
    • Export Citation
  • 8.

    de Courten-Myers GM, , Kleinholz M, & Holm P, et al: Hemorrhagic infarct conversion in experimental stroke. Ann Emerg Med 21:120126, 1992 de Courten-Myers GM, Kleinholz M, Holm P, et al: Hemorrhagic infarct conversion in experimental stroke. Ann Emerg Med 21:120–126, 1992

    • Search Google Scholar
    • Export Citation
  • 9.

    de Courten-Myers GM, , Kleinholz M, & Wagner KR, et al: Fatal strokes in hypoglycemic cats. Stroke 20:17071715, 1989 de Courten-Myers GM, Kleinholz M, Wagner KR, et al: Fatal strokes in hypoglycemic cats. Stroke 20:1707–1715, 1989

    • Search Google Scholar
    • Export Citation
  • 10.

    de Courten-Myers GM, , Myers RE, & Schoolfield L: Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke 19:623630, 1988 de Courten-Myers GM, Myers RE, Schoolfield L: Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats. Stroke 19:623–630, 1988

    • Search Google Scholar
    • Export Citation
  • 11.

    Duckrow RB, , Beard DC, & Brennan RW: Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18:5258, 1987 Duckrow RB, Beard DC, Brennan RW: Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18:52–58, 1987

    • Search Google Scholar
    • Export Citation
  • 12.

    Duverger D, & MacKenzie ET: The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab 8:449461, 1988 Duverger D, MacKenzie ET: The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab 8:449–461, 1988

    • Search Google Scholar
    • Export Citation
  • 13.

    Ginsberg MD, , Prado R, & Dietrich WD, et al: Hyperglycemia reduces the extent of cerebral infarction in rats. Stroke 18:570574, 1987 Ginsberg MD, Prado R, Dietrich WD, et al: Hyperglycemia reduces the extent of cerebral infarction in rats. Stroke 18:570–574, 1987

    • Search Google Scholar
    • Export Citation
  • 14.

    Harik SI, & LaManna JC: Vascular perfusion and blood-brain glucose transport in acute and chronic hyperglycemia. J Neurochem 51:19241929, 1988 Harik SI, LaManna JC: Vascular perfusion and blood-brain glucose transport in acute and chronic hyperglycemia. J Neurochem 51:1924–1929, 1988

    • Search Google Scholar
    • Export Citation
  • 15.

    Izumi Y, , Benz AM, & Clifford DB, et al: Nitric oxide inhibitors attenuate N-methyl-D-aspartate excitotoxicity in rat hippocampal slices. Neurosci Lett 135:227230, 1992 Izumi Y, Benz AM, Clifford DB, et al: Nitric oxide inhibitors attenuate N-methyl-D-aspartate excitotoxicity in rat hippocampal slices. Neurosci Lett 135:227–230, 1992

    • Search Google Scholar
    • Export Citation
  • 16.

    Kirino T: Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:5769, 1982 Kirino T: Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69, 1982

    • Search Google Scholar
    • Export Citation
  • 17.

    Kraft SA, , Larson CP Jr, & Shuer LM, et al: Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia. Stroke 21:447450, 1990 Kraft SA, Larson CP Jr, Shuer LM, et al: Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia. Stroke 21:447–450, 1990

    • Search Google Scholar
    • Export Citation
  • 18.

    LeMay DR, , Gehua L, & Zelenock GB, et al: Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke 19:14111419, 1988 LeMay DR, Gehua L, Zelenock GB, et al: Insulin administration protects neurologic function in cerebral ischemia in rats. Stroke 19:1411–1419, 1988

    • Search Google Scholar
    • Export Citation
  • 19.

    Levine SR, , Welch KMA, & Helpern JA, et al: Prolonged deterioration of ischemic brain energy metabolism and acidosis associated with hyperglycemia: human cerebral infarction studied by serial 31P NMR spectroscopy. Ann Neurol 23:416418, 1988 Levine SR, Welch KMA, Helpern JA, et al: Prolonged deterioration of ischemic brain energy metabolism and acidosis associated with hyperglycemia: human cerebral infarction studied by serial 31P NMR spectroscopy. Ann Neurol 23:416–418, 1988

    • Search Google Scholar
    • Export Citation
  • 20.

    Meyer JS, & Portnoy HD: Localized cerebral hypoglycemia simulating stroke. Neurology 8:601614, 1958 Meyer JS, Portnoy HD: Localized cerebral hypoglycemia simulating stroke. Neurology 8:601–614, 1958

    • Search Google Scholar
    • Export Citation
  • 21.

    Nedergaard M: Neuronal injury in the infarct border: a neuropathological study in the rat. Acta Neuropathol 73:267274, 1987 Nedergaard M: Neuronal injury in the infarct border: a neuropathological study in the rat. Acta Neuropathol 73:267–274, 1987

    • Search Google Scholar
    • Export Citation
  • 22.

    Nedergaard M, & Astrup J: Infarct rim: effect of hypoglycemia on direct current potential and [14C]2-deoxyglucose phosphorylation. J Cereb Blood Flow Metab 6:607615, 1986 Nedergaard M, Astrup J: Infarct rim: effect of hypoglycemia on direct current potential and [14C]2-deoxyglucose phosphorylation. J Cereb Blood Flow Metab 6:607–615, 1986

    • Search Google Scholar
    • Export Citation
  • 23.

    Nedergaard M, & Diemer NH: Focal ischemia of the rat brain, with special reference to the influence of plasma glucose concentration. Acta Neuropathol 73:131137, 1987 Nedergaard M, Diemer NH: Focal ischemia of the rat brain, with special reference to the influence of plasma glucose concentration. Acta Neuropathol 73:131–137, 1987

    • Search Google Scholar
    • Export Citation
  • 24.

    Nedergaard M, , Jakobsen J, & Diemer NH: Autoradiographic determination of cerebral glucose content, blood flow, and glucose utilization in focal ischemia of the rat brain: influence of the plasma glucose concentration. J Cereb Blood Flow Metab 8:100108, 1988 Nedergaard M, Jakobsen J, Diemer NH: Autoradiographic determination of cerebral glucose content, blood flow, and glucose utilization in focal ischemia of the rat brain: influence of the plasma glucose concentration. J Cereb Blood Flow Metab 8:100–108, 1988

    • Search Google Scholar
    • Export Citation
  • 25.

    O'Neill PA, , Davies I, & Fullerton KJ, et al: Stress hormone and blood glucose response following acute stroke in the elderly. Stroke 22:842847, 1991 O'Neill PA, Davies I, Fullerton KJ, et al: Stress hormone and blood glucose response following acute stroke in the elderly. Stroke 22:842–847, 1991

    • Search Google Scholar
    • Export Citation
  • 26.

    Paxinos G, & Watson C: The Rat Brain in Stereotaxic Coordinates. Sydney: Academic Press, 1982 Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. Sydney: Academic Press, 1982

    • Search Google Scholar
    • Export Citation
  • 27.

    Power MJ, , Fullerton KJ, & Stout RW: Blood glucose and prognosis of acute stroke. Age Ageing 17:164170, 1988 Power MJ, Fullerton KJ, Stout RW: Blood glucose and prognosis of acute stroke. Age Ageing 17:164–170, 1988

    • Search Google Scholar
    • Export Citation
  • 28.

    Prado R, , Ginsberg MD, & Dietrich WD, et al: Hyperglycemia increases infarct size in collaterally perfused but not endarterial vascular territories. J Cereb Blood Flow Metab 8:186192, 1988 Prado R, Ginsberg MD, Dietrich WD, et al: Hyperglycemia increases infarct size in collaterally perfused but not endarterial vascular territories. J Cereb Blood Flow Metab 8:186–192, 1988

    • Search Google Scholar
    • Export Citation
  • 29.

    Pulsinelli WA, , Levy DE, & Sigsbee B, et al: Increased damage after ischemic stroke in patients with hyperglycemia with or without diabetes mellitus. Am J Med 74:540544, 1983 Pulsinelli WA, Levy DE, Sigsbee B, et al: Increased damage after ischemic stroke in patients with hyperglycemia with or without diabetes mellitus. Am J Med 74:540–544, 1983

    • Search Google Scholar
    • Export Citation
  • 30.

    Robertson CS, & Grossman RG: Protection against spinal cord ischemia with insulin-induced hypoglycemia. J Neurosurg 67:739744, 1987 Robertson CS, Grossman RG: Protection against spinal cord ischemia with insulin-induced hypoglycemia. J Neurosurg 67:739–744, 1987

    • Search Google Scholar
    • Export Citation
  • 31.

    Siesjö BK: Hypoglycemia, brain metabolism, and brain damage. Diabetes Metab Rev 4:113141, 1988 Siesjö BK: Hypoglycemia, brain metabolism, and brain damage. Diabetes Metab Rev 4:113–141, 1988

    • Search Google Scholar
    • Export Citation
  • 32.

    Tracey F, , Crawford VLS, & Lawson JT, et al: Hyperglycaemia and mortality from acute stroke. J Med 86:439446, 1993 Tracey F, Crawford VLS, Lawson JT, et al: Hyperglycaemia and mortality from acute stroke. J Med 86:439–446, 1993

    • Search Google Scholar
    • Export Citation
  • 33.

    Voll CL, & Auer RN: The effect of postischemic blood glucose levels on ischemic brain damage in the rat. Ann Neurol 24:638646, 1988 Voll CL, Auer RN: The effect of postischemic blood glucose levels on ischemic brain damage in the rat. Ann Neurol 24:638–646, 1988

    • Search Google Scholar
    • Export Citation
  • 34.

    Voll CL, & Auer RN: Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab 11:10061014, 1991 Voll CL, Auer RN: Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab 11:1006–1014, 1991

    • Search Google Scholar
    • Export Citation
  • 35.

    Wagner KR, , Kleinholz M, & de Courten-Myers GM, et al: Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab 12:213222, 1992 Wagner KR, Kleinholz M, de Courten-Myers GM, et al: Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab 12:213–222, 1992

    • Search Google Scholar
    • Export Citation
  • 36.

    Woo J, , Lam CW, & Kay R, et al: The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol 47:11741177, 1990 Woo J, Lam CW, Kay R, et al: The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol 47:1174–1177, 1990

    • Search Google Scholar
    • Export Citation
  • 37.

    Woo E, , Ma JTC, & Robinson JD, et al: Hyperglycemia is a stress response in acute stroke. Stroke 19:13591364, 1988 Woo E, Ma JTC, Robinson JD, et al: Hyperglycemia is a stress response in acute stroke. Stroke 19:1359–1364, 1988

    • Search Google Scholar
    • Export Citation
  • 38.

    Yip PK, , He YY, & Hsu CY, et al: Effect of plasma glucose on infarct size in focal cerebral ischemia-perfusion. Neurology 41:899905, 1991 Yip PK, He YY, Hsu CY, et al: Effect of plasma glucose on infarct size in focal cerebral ischemia-perfusion. Neurology 41:899–905, 1991

    • Search Google Scholar
    • Export Citation
  • 39.

    Zasslow MA, , Pearl RG, & Shuer LM, et al: Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats. Stroke 20:519523, 1989 Zasslow MA, Pearl RG, Shuer LM, et al: Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats. Stroke 20:519–523, 1989

    • Search Google Scholar
    • Export Citation

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