The role of hyperglycemia in acute ischemic stroke

Neurocritical Care volume 5, pages153–158(2006)Cite this article

Abstract

Stroke remains a leading cause of death and long-term disability in the developed world. Reperfusion and anti-thrombotic therapies are of limited benefit for the majority of patients following acute ischemic stroke, and increasing interest has focused on therapeutic approaches that seek to modulate infarct evolution. Animal and human studies have linked hyperglycemia in the acute phase of ischemic stroke to worse clinical outcomes regardless of the presence of pre-existing diabetes mellitus. Experimental data suggest that elevated blood glucose may directly contribute to infarct expansion through a number of maladaptive metabolic pathways, and that treatment with insulin may attenuate these adverse effects. In this review, we analyze the relationship between elevated serum glucose and acute cerebrovascular ischemia, and critically appraise the potential of a clinical strategy that targets euglycemia in all acute stroke patients.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

References

  1. 1.

    Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med 2000;343:710–722.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035–2038.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Toni D, Sacchetti ML, Argentino, C, et al. Does hyperglycaemia play a role on the outcome of acute ischaemic stroke patients? J Neurol 1992;239:382–386.

    PubMed  CAS  Google Scholar 

  4. 4.

    Olsson T, et al. Prognosis after stroke in diabetic patients. A controlled prospective study. Diabetologia 1990;33:244–249.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Capes SE, et al. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 2001;32:2426–2432.

    PubMed  CAS  Google Scholar 

  6. 6.

    Malmberg K, et al. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: longterm results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999;99:2626–2632.

    PubMed  CAS  Google Scholar 

  7. 7.

    Gray CS, et al. Prevalence and prediction of unrecognised diabetes mellitus and impaired glucose tolerance following acute stroke. Age and Ageing 2004;33:71–77.

    PubMed  Article  Google Scholar 

  8. 8.

    Kiers L, Davis SM, Larkins R, et al. Stroke topography and outcome in relation to hyperglycaemia and diabetes. J Neurol Neurosurg Psychiatry 1992;55:263–270.

    PubMed  CAS  Google Scholar 

  9. 9.

    Weir CJ, et al. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study. BMJ 1997;314:1303–1306.

    PubMed  CAS  Google Scholar 

  10. 10.

    Jorgensen H, et al. Stroke in patients with diabetes. The Copenhagen Stroke Study. Stroke 1994;25:1977–1984.

    PubMed  CAS  Google Scholar 

  11. 11.

    van Kooten F, et al. Hyperglycemia in the acute phase of stroke is not cuased by stress. Stroke 1993;24:1129–1132.

    PubMed  Google Scholar 

  12. 12.

    Murros K, et al. Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction, J Neurol Sci 1992;111:59–64.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Murros K, Fogelholmd R. Diabetes and stress hyperglycaemia in stroke. J Neurol Neurosurg Psychiatry 1993;56:428.

    PubMed  CAS  Google Scholar 

  14. 14.

    Woo E, et al. Hyperglycemia is a stress response in acute stroke. Stroke 1988;19:1359–1364.

    PubMed  CAS  Google Scholar 

  15. 15.

    O'Neill PA, et al. Stress hormone and blood glucose response following acute stroke in the elderly. Stroke 1991;22:842–847.

    PubMed  Google Scholar 

  16. 16.

    Myers RE, Yamaguchi S. Nervous system effects of cardiac arrest in monkeys. Preservation of vision. Arch Neurol 1977;34:65–74.

    PubMed  CAS  Google Scholar 

  17. 17.

    Pulsinelli WA, et al. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 1982;32:1239–1246.

    PubMed  CAS  Google Scholar 

  18. 18.

    Gisselsson L, Smith ML, Siesjo BK. Hyperglycemia and focal brain ischemia. J Cereb Blood Flow Metab 1999;19:288–297.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Lin B, Ginsberg MD, Busto R.. Hyperglycemic exacerbation of neuronal damage following forebrain ischemia: microglial, astrocytic and endothelial alterations. Acta Neuropathol (Berl) 1998;96:610–620.

    Article  CAS  Google Scholar 

  20. 20.

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

    PubMed  Google Scholar 

  21. 21.

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

    PubMed  Google Scholar 

  22. 22.

    Prado R, Ginsberg MD, Dietrich WD, Watson BD, Busto R, et al. Hyperglycemia increases infarct size in collaterally perfused but not end-arterial vascular territories. J Cereb Blood Flow Metab 1988;8:186–192.

    PubMed  CAS  Google Scholar 

  23. 23.

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

    PubMed  CAS  Google Scholar 

  24. 24.

    Helgason CM. Blood glucose and stroke. Stroke 1988;19:1049–1053.

    PubMed  CAS  Google Scholar 

  25. 25.

    Nedergaard M, Gjedde A, Diemer NH. Hyperglycaemia protects against neuronal injury around experimental brain infarcts. Neurol Res 1987;9:241–244.

    PubMed  CAS  Google Scholar 

  26. 26.

    Auer RN. Insulin, blood glucose levels, and ischemic brain damage. Neurology 1998;51:S39-S43.

    PubMed  CAS  Google Scholar 

  27. 27.

    Hamilton MG, Tranmer BI, Auer RN. Insulin reduction of cerebral infarction due to transient focal ischemia. J Neurosurg 1995;82:262–268.

    PubMed  CAS  Article  Google Scholar 

  28. 28.

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

    PubMed  CAS  Google Scholar 

  29. 29.

    Voll CL, Whishaw IQ, Auer RN. Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989;20:646–651.

    PubMed  CAS  Google Scholar 

  30. 30.

    Wass CT, Scheithauer BW, Bronk JT, Wilson RM, Lanier WL, et al. Insulin treatment of corticosteroid-associated hyperglycemia and its effect on outcome after forebrain ischemia in rats. Anesthesiology 1996;84:644–651.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Zhu CZ, Auer RN. Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia. J Cereb Blood Flow Metab 1994;14:237–242.

    PubMed  CAS  Google Scholar 

  32. 31a.

    Scott JF, Robinson GM, French JM, O'Connell JE, Alberti K, Gray CS. Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: The glucose in sulin in stroke trial (GIST). Stroke 1999;30:793–799.

    PubMed  CAS  Google Scholar 

  33. 32.

    Siesjo BK, Katsura KI, Kristian T, Li PA, Siesjo P, et al. Molecular mechanisms of acidosis-mediated damage. Acta Neurochir Suppl 1996;66:8–14.

    PubMed  CAS  Google Scholar 

  34. 33.

    Anderson RE, Tan WK, Martin HS, Meyer FB, et al. Effects of glucose and PaO2 modulation on cortical intracellular acidosis, NADH redox state, and infarction in the ischemic penumbra. Stroke 1999;30:160–170.

    PubMed  CAS  Google Scholar 

  35. 34.

    Hoxworth JM, Xu K, Zhou Y, Lust WD, LaManna JC, et al. Cerebral metabolic profile, selective neuron loss, and survival of acute and chronic hyperglycemic rats following cardiac arrest and resuscitation. Brain Res 1999;821:467–479.

    PubMed  Article  CAS  Google Scholar 

  36. 35.

    Kraig RP, Petito CK, Plum F, Pulsinelli WA, et al. Hydrogen ions kill brain at concentrations reached in ischemia. J Cereb Blood Flow Metab 1987;7:379–386.

    PubMed  CAS  Google Scholar 

  37. 36.

    Petito CK, Kraig RP, Pulsinelli WA, Light and electron microscopic evaluation of hydrogen ion-induced brain necrosis. J Cereb Blood Flow Metab 1987;7:625–632.

    PubMed  CAS  Google Scholar 

  38. 37.

    Benveniste H. The excitotoxin hypothesis in relation to cerebral ischemia. Cerebrovasc Brain Metab Rev 1991;3:213–245.

    PubMed  CAS  Google Scholar 

  39. 38.

    Li PA, Shuaib A, Miyashita H, He QP, Siesjo BK, Warner DS, et al. Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia. Stroke 2000;31:183–192.

    PubMed  CAS  Google Scholar 

  40. 39.

    Nedergaard M. Spleading depression as a contributor to ischemic brain damage. Adv Neurol 1996;71:75–84.

    PubMed  CAS  Google Scholar 

  41. 40.

    Koistinaho J, Pasonen S, Yrjanheikki J, Chan PH, et al. Spreading depression-induced gene expression is regulated by plasma glucose. Stroke 1999;30:114–119.

    PubMed  CAS  Google Scholar 

  42. 41.

    Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Horwitz RI, et al. Insulin resistance and risk for stroke. Neurology 2002;59:809–815.

    PubMed  CAS  Google Scholar 

  43. 42.

    Kawai N, Keep RF, Betz AL. Hyperglycemia and the vascular effects of cerebral ischemia. Acta Neurochir Suppl 1997;70:27–29.

    PubMed  CAS  Google Scholar 

  44. 43.

    Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997;100:1230–1239.

    PubMed  CAS  Article  Google Scholar 

  45. 44.

    Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994;343:155–158.

    PubMed  Article  CAS  Google Scholar 

  46. 45.

    Kawai N, Keep RF, Betz AL. Effects of hyperglycemia on cerebral blood flow and edema formation after carotid artery occlusion in Fischer 344 rats. Acta Neurochir Suppl 1997;70:34–36.

    PubMed  CAS  Google Scholar 

  47. 46.

    Dietrich WD, Alonso O, Busto R. Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain ischemia in rats. Stroke 1993;24:111–116.

    PubMed  CAS  Google Scholar 

  48. 47.

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

    Article  Google Scholar 

  49. 48.

    Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab 1998;18:583–609.

    PubMed  Article  CAS  Google Scholar 

  50. 49.

    Barber PA, Darby DG, Desmond PM, et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology 1998;51:418–426.

    PubMed  CAS  Google Scholar 

  51. 50.

    Parsons MW, Barber PA, Desmond M, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol 2002;52:20–28.

    PubMed  Article  Google Scholar 

  52. 51.

    Ginsberg MD. Hyperglycemia and stroke outcome: vindication of the ischemic penumbra. Ann Neurol 2002;52:5–6.

    PubMed  Article  Google Scholar 

  53. 52.

    Kase CS, Furlan AJ, Wechsler LR, et al. Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT II trial. Neurology 2001;57:1603–1610.

    PubMed  CAS  Google Scholar 

  54. 53.

    Demchuk AM, Morgenstern LB, Krieger DW, et al. Serum glucose level and diabetes predict tissue plasminogen activatorrelated intracerebral hemorrhage in acute ischemic stroke. Stroke 1999;30:34–39.

    PubMed  CAS  Google Scholar 

  55. 54.

    Lindsberg PJ, Kaste M. Thrombolysis for acute stroke. Curr Opin Neurol 2003;16:73–80.

    PubMed  Article  Google Scholar 

  56. 55.

    Lindsberg PJ, Soinne L, Roine RO, et al. Community-based thrombolytic therapy of acute ischemic stroke in Helsinki. Stroke 2003;34:1443–1449.

    PubMed  Article  CAS  Google Scholar 

  57. 56.

    Bruno A, Levine SR, Frankel MR, et al. Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59:669–674.

    PubMed  CAS  Google Scholar 

  58. 57.

    Alvarez-Sabin J, Molina CA, Montaner J, et al. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator--treated patients. Stroke 2003;34:1235–1241.

    PubMed  Article  Google Scholar 

  59. 58.

    Bruno A, Biller J, Adams HP, et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology 1999;52:280–284.

    PubMed  CAS  Google Scholar 

  60. 59.

    Christensen H, Boysen G. Blood glucose increases early after stroke onset: a study on serial measurements of blood glucose in acute stroke. Eur J Neurol 2002;9:297–301.

    PubMed  Article  CAS  Google Scholar 

  61. 60.

    Baird TA, Parsons MW, Phanh T, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke, 2003;34:2208–2214.

    PubMed  Article  CAS  Google Scholar 

  62. 61.

    Williams LS, Rotich J, Qi R, et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology 2002;59:67–71.

    PubMed  CAS  Google Scholar 

  63. 62.

    Adams HP, Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003;34:1056–1083.

    PubMed  Article  Google Scholar 

  64. 63.

    Hack W, Kaste M, Bogousslavsky J, et al. European Stroke Initiative recommendations for stroke management-update 2003. Cerebrovasc Dis 2003;16:311–337.

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

  1. Department of Emergency Medicine, Mayo Clinic, 55905, Rochester, MN

    Rachel M. Gilmore & Latha G. Stedd

Authors
  1. Rachel M. Gilmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Latha G. Stedd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Latha G. Stedd.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gilmore, R.M., Stedd, L.G. The role of hyperglycemia in acute ischemic stroke. Neurocrit Care 5, 153–158 (2006). https://doi.org/10.1385/NCC:5:2:153

Download citation

Key Words

  • Hyperglycemia
  • stroke, insulin, diabetes mellitus