Quick search in Citations
This JournalAnywhereCitation
Advanced Search
Commentary
Originally Published 23 November 2005
Free Access

Hyperglycemia, Insulin, and Acute Ischemic Stroke: A Mechanistic Justification for a Trial of Insulin Infusion Therapy

Rajesh Garg, MD, Ajay Chaudhuri, MD, Frederick Munschauer, MD, and Paresh Dandona, MD, PhDAuthor Info & Affiliations
Stroke
Volume 37, Number 1
https://doi.org/10.1161/01.STR.0000195175.29487.30
Track CitationsAdd to favorites
PDF/EPUB

Abstract

Background and Purpose— Hyperglycemia is associated with increased mortality and morbidity in acute ischemic stroke.
Summary of Review— Hyperglycemia induces a pro-oxidative and proinflammatory state that can cause direct neuronal toxicity. Hyperglycemia-mediated increase in matrix metalloproteinase-9 can cause neuronal damage by an increase in cerebral edema. Moreover, hyperglycemia may be responsible for a procoagulant state that can further compromise blood supply to the penumbral areas in acute ischemic stroke. Insulin infusion has an effect that is opposite to that of hyperglycemia. It not only lowers blood glucose levels but also exerts an antioxidant and anti-inflammatory effect. Insulin also improves NO production and results in improved blood circulation to the ischemic areas. This article focuses on the potential mechanisms underlying the injurious effects of glucose and the beneficial effects of insulin.
Conclusions— In the absence of other potential beneficial therapies, there is an urgency to institute trials with insulin infusion in acute ischemic stroke.
Hyperglycemia without pre-existing diabetes mellitus has been recognized in acute stroke for a long time.1,2 Whereas diabetes mellitus is clearly a risk factor for the occurrence of stroke3 and for its poor prognosis,4 hyperglycemia without pre-existing diabetes mellitus is also linked to increased mortality and morbidity in stroke patients.2 However, there is no consensus on whether hyperglycemia per se is the cause of poor stroke outcomes.5 Results of the recent clinical trials on insulin infusion therapy in other acute conditions such as myocardial infarction6,7 and critically ill patients8 have rekindled interest in the possible therapeutic efficacy of insulin in hyperglycemia associated with acute stroke. Although insulin lowers blood glucose levels, it has other important effects that may influence the underlying pathogenic mechanisms in stroke. This article reviews the proposed mechanisms underlying adverse outcomes of ischemic stroke with hyperglycemia and possible effects of insulin infusion in improving stroke outcomes. Although hyperglycemia is relevant in intracerebral hemorrhage,9 the pathogenic mechanisms leading to intracerebral hemorrhage are different from those leading to ischemic stroke, and intracerebral hemorrhage is not a focus of this review.

Hyperglycemia and Stroke Outcome

In a retrospective study in 1976, Melamed showed that hyperglycemia was present in 28% of patients with stroke in the absence of a previous history of diabetes.1 The incidence and degree of hyperglycemia were related to the severity of acute stroke and hospital mortality was significantly higher in hyperglycemic patients.1 Since then, the association between hyperglycemia and stroke outcome has been published in many more studies and reviewed in a meta-analysis by Capes et al.2 This meta-analysis found that the relative risk of death after ischemic stroke with admission blood glucose levels >6.1 to 7.0 mmol/L (110 to 126 mg/dL) was 3.28 (95% CI, 2.32 to 4.64).2 There was also a greater risk of poor functional recovery in the hyperglycemic patients.2 Several recent studies in patients treated with thrombolytic therapy for acute ischemic stroke have again demonstrated a profound effect of hyperglycemia on stroke outcomes10–15 (Table). Hyperglycemic effects are more prominent in nonlacunar stroke than lacunar stroke. In a large study involving 1259 patients with acute ischemic stroke, hyperglycemia was associated with worse clinical outcomes only in nonlacunar stroke.16 Although in some other studies, the investigators concluded that hyperglycemia was simply a stress response to acute stroke,17,18 poor clinical outcome in hyperglycemic patients is quite evident.
Studies on the Effect of Hyperglycemia in Acute Stroke Patients Treated With Thrombolytic Therapy
ReferencenGlucose Level CutoffStudy ParametersResultsP ValueAdditional Features of the Study
TT indicates thrombolytic therapy; BGT, blood glucose test; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; mRS, modified Rankin scale.
Leigh et al102018.3 mmol/L at admissionChange in NIHSS at 24 h ≥−4=good outcome; ≥+4=poor outcomeOR for hyperglycemia in poor outcome compared with good outcome=5.67 BGT in good outcome: 138 mg/dL and in poor outcome: 173 mg/dL0.009 0.024TT within 6 h
Saposnik et al112128.0 mmol/L at admissionChange in NIHSS at 24 h <−3=lack of improvementOR for lack of improvement in hyperglycemia=2.94 BGT in lack of improvement vs improvement: 147±55 mg/dL vs 105±38 mg/dL0.003 0.003TT within 3 h
Alvarez-Sabin et al12737.7 mmol/L at admissionChange in NIHSS at 24 h mRS at 3 moCorrelation between NIHSS and BGT in patients with successful reperfusion: r=−0.43 OR for poor outcome (mRS 3–6) at 3 months for hyperglycemic reperfused group=8.40.019 0.005TT in 3 h
Bruno et al15624Admission BGTNIHSS change of >4 at 3 moOR for neurological improvement per 100 mg/dL increase in BGT=0.760.01TT in 3 h (NINDS rtPA trial)
Els et al603110 mmol/L at admissionInfract size by diffusion-weighted MRI at admission, day 3 and day 7 NIHSS at 28 daysIncrease in infarct size from baseline in hyperglycemic vs normoglycemic group 39.9%±17.7 vs 27.1±14.1% NIHSS in hyperglycemic vs normoglycemic group 7.4 vs 4<0.05 <0.05TT within 3 h

Etiology of Hyperglycemia in Acute Stroke

Hyperglycemia after acute stroke may be attributable to several underlying mechanisms. These include: a nonspecific reaction to acute stress; autonomic, hormonal, and metabolic alterations as a result of tissue injury; uncovering of underlying latent diabetes by the acute stroke; activation of the hypothalamo-hypophyseal-adrenal axis attributable to a direct effect of brain ischemia on the pituitary; and irritation of the glucose regulatory centers in the brain by a stroke. By far, the most popular belief is that stroke related hyperglycemia is a stress response with activation of the hypothalamo-hypophyseal-adrenal axis, which leads to an increase in cortisol and catecholamines. According to this simple explanation, the poor stroke outcome in patients with hyperglycemia may be because more severe stroke induces higher levels of catecholamines and corticosteroids and represents an epiphenomenon associated with a poor outcome rather than having any causal relationship.18 However, data have not been consistent on the relationship between hyperglycemia and stress hormones in stroke; 1 study showed that hyperglycemia may be a stress response,17 whereas another showed an absence of such an association.19 Hyperglycemia in acute stroke is probably the result of multiple factors, including cytokine-induced resistance to insulin action.

Mechanisms of Hyperglycemia-Mediated Brain Damage

The possible mechanisms of glucose-mediated increase in cerebral infarct size include poor blood flow to the ischemic penumbra;20,21 changes in cerebral metabolism;22 increase in N-methyl-d-aspartate (NMDA) receptor–mediated calcium entry into the neurons;23 increased local edema;24 and, most important, glucose-mediated increase in oxidative stress and inflammation.25,26 These mechanisms may well be interrelated.

Hyperglycemia-Associated Reduction in Perfusion

In experimental rats, the injection of intraperitoneal glucose to produce hyperglycemia during induction of ischemia of the brain was associated with a 24% reduction in regional blood flow, whereas injection of d-mannitol to produce an equivalent elevation of plasma osmolality reduced cerebral blood flow by only 10% when compared with controls that received normal saline.20 Additionally, hyperglycemia is seen to cause reduction in blood circulation to the marginal ischemic areas after occlusion of the middle cerebral artery.21 This suggests that penumbra around the infarct area converts to infarct in hyperglycemia. This phenomenon is analogous to the defect in cerebral blood flow in diabetics. CO2-induced increase in cerebral blood flow is decreased in diabetics.27 CO2-induced cerebral vasodilatation is mediated through NO, and diabetics are known to have decreased endothelial NO production. Moreover, glucose-induced reactive oxygen species (ROS) can neutralize NO in the vessel wall (Figure 1). Hyperglycemia-induced reduction in cerebral blood flow may be mediated through neutralization of NO or its impaired production.
Figure 1. Glucose-mediated proinflammatory and procoagulant effects.

Hyperglycemia-Associated Metabolic Alteration

Changes in cerebral metabolism may be the other mechanism of increased cerebral damage by hyperglycemia. Hyperglycemic cats had significantly reduced cerebral high-energy phosphates, elevated lactic acid, and larger ischemic lesions in the occluded middle cerebral artery territory.28 Hypometabolism of the ischemic focus is seen early and extends more into the penumbra in hyperglycemic animals when compared with normoglycemic animals.22 In a study on humans, cerebral hypometabolism assessed by positron emission tomography in acute ischemic cerebral infarction was more severe in patients with glucose concentrations >6.7 mmol/L.29 Hypometabolism may be related to lactic acid accumulation leading to mitochondrial dysfunction in the ischemic tissue. Hyperglycemia during cerebral ischemia leads to higher lactic acid accumulation in the ischemic tissue because the tissue glucose levels get depleted during ischemia in the normoglycemic state.30 Hyperglycemia may also directly affect mitochondrial function in the ischemic penumbra and cause significant intracellular brain acidosis.31 Cortical acidosis leads to the recruitment of the ischemic penumbra into the infarct zone.

Hyperglycemia-Associated Impaired Calcium Homeostasis

Excitatory amino acids, notably glutamate, play a central role in neuronal death by activation of postsynaptic glutamate receptors, particularly NMDA receptors. This activation leads to an excessive influx of calcium through ion channels, mitochondrial injury, and eventual cell death. It has been shown that the rise in extracellular glutamate concentrations after forebrain ischemia was more pronounced in hyperglycemic rats than in normoglycemic animals.23 The difference was observed in the neocortical regions of the brain and correlated with increased cell damage.23 Thus, hyperglycemia, by increasing the availability of glutamate, may induce calcium-mediated neuronal cell death. Hyperglycemia may also be harmful to calcium recovery during the early perfusion period after focal cerebral ischemia, thereby increasing intracellular calcium for a longer time.32

Inflammation and Free Radical–Associated Injury

Hyperglycemia is known to be associated with inflammation and oxidative stress (Figure 1). A 75-g glucose challenge has been shown to induce an increase in superoxide generation by leukocytes by 140% over the basal in addition to increasing p47phox expression, a subunit of NADPH oxidase, the enzyme that converts molecular O2 to the superoxide radical.25 Glucose intake also results in comprehensive inflammation as reflected in an increase in nuclear factor κB (NF-κB) binding and a decrease in inhibitor kappa B (IκB) expression.26 NF-κB is a nuclear transcription factor that normally stays in the cytoplasm in association with IκB.33 In response to an inflammatory stimulus, there is an increase in IκB kinase-α and IκB kinase-β, which phosphorylate IκB and result in its ubiquitination and proteosomal degradation. Degradation of IκB results in release of NF-κB and in its translocation from the cytoplasm to the nucleus, where it stimulates the transcription of proinflammatory cytokines.33 Activation of NF-κB and superoxide generation have been shown to be involved in tissue injury after occlusion of middle cerebral artery.34–36 NF-κB activation leads to increased production of inflammatory cytokines and chemokines such as tumor necrosis factor-α and monocyte chemoattractant protein (MCP-1). This attracts leukocytes to the ischemic area. Superoxide radicals can cause direct cell damage through lipid peroxidation, protein carbonylation, and DNA damage. Superoxide also neutralizes NO produced by endothelium by converting NO to peroxinitrite. NO is critical in maintenance of blood flow to the ischemic brain tissue by causing vasodilatation of arteries. Glucose intake also causes an increase in 2 other proinflammatory transcription factors: activator protein-1 (AP-1) and early growth response-1 (Egr-1).37 AP-1 regulates the transcription of matrix metalloproteinases (MMPs), whereas Egr-1 modulates the transcription of tissue factor (TF). Thus, glucose intake increases the expression of MMP-2 and MMP-9 as well as that of TF.37 MMP-9, also involved in the process of central spreading depression38 after an acute stroke, plays a significant role in brain damage by increasing brain edema. Central spreading depression is characterized by neuronal and glial depolarization, which is followed 3 to 6 hours later by an increase in the expression of MMP-9 initially in the cortical blood vessels, spreading later to neuronal layers and finally to the pia and the arachnoid.38 The increase in MMP-9 results in a reduction of laminin, endothelial barrier antigen, and the zona occludens.38 These 3 proteins are important in the maintenance of blood–brain barrier. The decrease in their concentration affects the integrity of the blood–brain barrier and an increase in the permeability of the barrier, resulting in edema with the leakage of plasma proteins and inflammatory cells. Stroke patients with hyperglycemia indeed develop more pronounced cerebral edema.24 Glucose-induced increase in TF can activate the extrinsic pathways of coagulation. Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is known to be increased in hyperglycemia. The increase in TF and PAI-1 can worsen ischemic damage by promoting coagulation in local capillaries. Thus, hyperglycemia may increase the cerebral damage by disrupting the microcirculation and upregulating the inflammatory and the related thrombotic/fibrinolytic mechanisms in brain.

Insulin Treatment of Acute Stroke

It has been demonstrated in animal models that during acute focal and global ischemia, insulin therapy reduces ischemic brain damage and can be neuroprotective.39–41 Whereas insulin lowers the glucose levels and thus reverses the damaging effects of glucose, there is an emerging body of evidence that there may be direct benefits of insulin itself. In a global ischemic model, insulin reduced neuronal necrosis regardless of its effect on glucose levels.40 In addition, insulin, and to a lesser extent insulin-like growth factor-1, reduced ischemic damage when injected directly into the brain ventricles.42 Therefore, it has been suggested that insulin has a direct neuroprotective effect on central nervous system parenchyma.
Insulin has recently been shown to possess a potent anti-inflammatory effect in vitro and in vivo (Figure 2).43,44 Insulin has been shown to suppress several proinflammatory transcription factors, such as NF-κB, Egr-1, and AP-1, and the corresponding genes regulated by them that mediate inflammation.44,45 Insulin has also been shown to suppress ROS generation, p47phox expression in the circulating mononuclear cells, as well as plasma concentrations of intercellular adhesion molecule-1 (ICAM-1) and MCP-1.44 In addition to its inhibitory effect on AP-1 and Egr-1, insulin suppresses their regulated gene products as indicated by a fall in plasma concentration of MMP-9, TF, and PAI-1,45–47 an effect diametrically opposite to that of glucose. MMP-9 is involved in the phenomenon of central spreading depression as noted above. MMP-9 null mice have smaller brain infarct volumes after the experimental induction of a stroke.38 Thus, clearly, MMP-9 is a cardinal mediator of these effects and a reduction in its activity or expression by insulin could be a rational therapeutic approach in the prevention or the limitation of ischemia-related damage to the brain. Insulin also causes a similar reduction in the plasma concentration of vascular endothelial growth factor (VEGF), a cytokine that induces an increase in the expression of MMP-9.47 It has also been shown that VEGF can cause the loss of endothelial cell tight junctions.48 It is possible that VEGF and MMP-9 may act in a synergistic fashion to cause a disruption of the blood–brain barrier during ischemia because hypoxia is the major factor inducing an increase in the expression of VEGF.49 The fact that insulin suppresses MMP-9 and VEGF, both of which are the mediators of ischemic damage, suggests strongly that it may have a beneficial role in the treatment of an acute stroke. Moreover, insulin-mediated suppression of TF and PAI-1 can produce an anticoagulant effect. High catecholamine levels in the circulation during acute stroke can increase the production of free fatty acids. Free fatty acids decrease the generation and the stability of prostacyclin,50 which is important for not only vasodilatation but also for preventing platelet aggregation. Insulin inhibits lipolysis, leading to a decrease in plasma-free fatty acids and thus may exert an antiplatelet and anticoagulant effect. The anti-inflammatory effect of insulin has been confirmed by us in acute myocardial infarction.51
Figure 2. Anti-inflammatory, anticoagulant, and vasodilatory effect of insulin.
In addition to suppressing the mediators of inflammation and coagulation, insulin has also been shown to increase endothelial NO release and the expression of NO synthase (NOS) expression in the endothelial cells.52,53 Insulin was also recently shown to increase the expression of neuronal NOS in astrocytes as well as neurons.54 Generation of NO would potentially help in vasodilatation and improved blood flow to the penumbra but also result in decreased production of ICAM-1. In addition, insulin has a direct inhibitory effect on platelet aggregation, mediated through the NO–guanylate cyclase-cGMP pathway activated by NO generated by NOS in platelets.55 The antiplatelet effect of insulin may also potentially mediate further anti-inflammatory activity because platelet aggregation leads to the release of CD40 ligand (also called CD 154) contained in α-granules of platelets. CD40 ligand is a major mediator of inflammation.

Conclusions

Hyperglycemia is detrimental in acute stroke, whereas insulin infusion can reverse this effect. Hyperglycemia induces an inflammatory state, whereas insulin has an anti-inflammatory effect. Insulin may help protect the brain not only through its glucose-lowering effect but also through its direct anti-inflammatory effect. Strongest evidence in favor of insulin use has come from the clinical trials in intensive care units and in acute myocardial infarction patients.7,8 Insulin infusion can be safely administered to acute stroke patients.56,57 In a recent study, intravenous insulin infusion effectively brought down blood glucose from a mean of 14.7±4.9 to 7.3±1.1 mmol/L without any problems.57 Although results from controlled clinical trials assessing insulin therapy in patients with stroke are still lacking, the available data favor the need for avoiding hyperglycemia in patients with acute stroke. The ongoing Glucose Insulin in Stroke Trial (GIST)–UK trial56,58 was set up to answer the question whether correction of hyperglycemia is beneficial in acute stroke. The trial started in 1999 with a target to enroll 1200 patients by 2002.59 The demonstration of mortality benefit, the primary end point of this trial, requires a large number of patients. However, GIST has been slow in patient recruitment. By the time the results of GIST trial come out, it may no longer be relevant because the control group has a very high target blood glucose level (17 mmol/L or 306 mg/dL), which is unacceptable in the current guidelines for any hospitalized patient. If the primary end points were nonmortality outcomes or cerebral infarct size measured by diffusion perfusion–weighted MRI, much smaller numbers will be needed. A trial of insulin infusion involving 400 patients will have enough power to detect any nonmortality clinical benefits as well as 20% difference in infarct size, assuming a mean infract size of 15 cm3 and an SD of 10. We suggest excluding intracerebral hemorrhage from such a trial and conduct a separate study for this condition. In the absence of potential beneficial therapies for acute ischemic stroke, there is an urgency to institute these trials with a drug that has no side effects other than potential hypoglycemia.

Acknowledgments

We are thankful to Dr Neeta Garg for valuable suggestions.

References

1.
Melamed E. Reactive hyperglycemia in patients with acute stroke. J Neurol Sci. 1976; 29: 267–275.
Crossref
PubMed
Google Scholar
2.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001; 32: 2426–2432.
Crossref
PubMed
Google Scholar
3.
Qureshi AI, Giles WH, Croft JB. Impaired glucose tolerance and the likelihood of nonfatal stroke and myocardial infarction: the Third National Health and Nutrition Examination Survey. Stroke. 1998; 29: 1329–1332.
Crossref
PubMed
Google Scholar
4.
Heuschmann PU, Kolominsky-Rabas PL, Misselwitz B, Hermanek P, Leffmann C, Janzen RW, Rother J, Buecker-Nott HJ, Berger K. Predictors of in-hospital mortality and attributable risks of death after ischemic stroke: the German Stroke Registers Study Group. Arch Intern Med. 2004; 164: 1761–1768.
Crossref
PubMed
Google Scholar
5.
Toni D, Sacchetti ML, Argentino C, Gentile M, Cavalletti C, Frontoni M, Fieschi C. Does hyperglycemia play a role on the outcome of acute ischemic stroke patients? J Neurol. 1992; 239: 382–386.
Crossref
PubMed
Google Scholar
6.
Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG, Corvalan R, Isea JE, Romero G. Metabolic modulation of acute myocardial infarction. The ecla (estudios cardiologicos latinoamerica) collaborative group. Circulation. 1998; 98: 2227–2234.
Crossref
PubMed
Google Scholar
7.
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (digami study): effects on mortality at 1 year. J Am Coll Cardiol. 1995; 26: 57–65.
Crossref
PubMed
Google Scholar
8.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the surgical intensive care unit. N Engl J Med. 2001; 345: 1359–1367.
Crossref
PubMed
Google Scholar
9.
Woo J, Lam CW, Kay R, Wong AH, Teoh R, Nicholls MG. The influence of hyperglycemia and diabetes mellitus on immediate and 3-month morbidity and mortality after acute stroke. Arch Neurol. 1990; 47: 1174–1177.
Crossref
PubMed
Google Scholar
10.
Leigh R, Zaidat OO, Suri MF, Lynch G, Sundararajan S, Sunshine JL, Tarr R, Selman W, Landis DM, Suarez JI. Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy. Stroke. 2004; 35: 1903–1907.
Crossref
PubMed
Google Scholar
11.
Saposnik G, Young B, Silver B, Di Legge S, Webster F, Beletsky V, Jain V, Nilanont Y, Hachinski V. Lack of improvement in patients with acute stroke after treatment with thrombolytic therapy: predictors and association with outcome. J Am Med Assoc. 2004; 292: 1839–1844.
Crossref
PubMed
Google Scholar
12.
Alvarez-Sabin J, Molina CA, Montaner J, Arenillas JF, Huertas R, Ribo M, Codina A, Quintana M. Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator–treated patients. Stroke. 2003; 34: 1235–1241.
Crossref
PubMed
Google Scholar
13.
Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, Colman PG, Chambers BR, Davis SM. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke. 2003; 34: 2208–2214.
Crossref
PubMed
Google Scholar
14.
Williams LS, Rotich J, Qi R, Fineberg N, Espay A, Bruno A, Fineberg SE, Tierney WR. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology. 2002; 59: 67–71.
Crossref
PubMed
Google Scholar
15.
Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC, Lyden PD, Broderick JP, Kwiatkowski TG, Fineberg SE. Admission glucose level and clinical outcomes in the NINDS rt-PA stroke trial. Neurology. 2002; 59: 669–674.
Crossref
PubMed
Google Scholar
16.
Bruno A, Biller J, Adams HP Jr, Clarke WR, Woolson RF, Williams LS, Hansen MD. Acute blood glucose level and outcome from ischemic stroke. Trial of org 10172 in acute stroke treatment (TOAST) investigators. Neurology. 1999; 52: 280–284.
Crossref
PubMed
Google Scholar
17.
Tracey F, Crawford VL, Lawson JT, Buchanan KD, Stout RW. Hyperglycaemia and mortality from acute stroke. Q J Med. 1993; 86: 439–446.
PubMed
Google Scholar
18.
Murros K, Fogelholm R, Kettunen S, Vuorela AL, Valve J. Blood glucose, glycosylated haemoglobin, and outcome of ischemic brain infarction. J Neurol Sci. 1992; 111: 59–64.
Crossref
PubMed
Google Scholar
19.
van Kooten F, Hoogerbrugge N, Naarding P, Koudstaal PJ. Hyperglycemia in the acute phase of stroke is not caused by stress. Stroke. 1993; 24: 1129–1132.
Crossref
PubMed
Google Scholar
20.
Duckrow RB, Beard DC, Brennan RW. Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol. 1985; 17: 267–272.
Crossref
PubMed
Google Scholar
21.
Kawai N, Keep RF, Betz AL, Nagao S. Hyperglycemia induces progressive changes in the cerebral microvasculature and blood–brain barrier transport during focal cerebral ischemia. Acta Neurochir Suppl. 1998; 71: 219–221.
PubMed
Google Scholar
22.
Folbergrova J, Memezawa H, Smith ML, Siesjo BK. Focal and perifocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. J Cereb Blood Flow Metab. 1992; 12: 25–33.
Crossref
PubMed
Google Scholar
23.
Li PA, Shuaib A, Miyashita H, He QP, Siesjo BK, Warner DS. Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia. Stroke. 2000; 31: 183–192.
Crossref
PubMed
Google Scholar
24.
Berger L, Hakim AM. The association of hyperglycemia with cerebral edema in stroke. Stroke. 1986; 17: 865–871.
Crossref
PubMed
Google Scholar
25.
Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab. 2000; 85: 2970–2973.
Crossref
PubMed
Google Scholar
26.
Dhindsa S, Tripathy D, Mohanty P, Ghanim H, Syed T, Aljada A, Dandona P. Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappab in mononuclear cells. Metabolism. 2004; 53: 330–334.
Crossref
PubMed
Google Scholar
27.
Dandona P, James IM, Newbury PA, Woollard ML, Beckett AG. Cerebral blood flow in diabetes mellitus: evidence of abnormal cerebrovascular reactivity. BMJ. 1978; 2: 325–326.
Crossref
PubMed
Google Scholar
28.
Chew W, Kucharczyk J, Moseley M, Derugin N, Norman D. Hyperglycemia augments ischemic brain injury: in vivo MR imaging/spectroscopic study with nicardipine in cats with occluded middle cerebral arteries. AJNR Am J Neuroradiol. 1991; 12: 603–609.
PubMed
Google Scholar
29.
Kushner M, Nencini P, Reivich M, Rango M, Jamieson D, Fazekas F, Zimmerman R, Chawluk J, Alavi A, Alves W. Relation of hyperglycemia early in ischemic brain infarction to cerebral anatomy, metabolism, and clinical outcome. Ann Neurol. 1990; 28: 129–135.
Crossref
PubMed
Google Scholar
30.
Wagner KR, Kleinholz M, de Courten-Myers GM, Myers RE. Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab. 1992; 12: 213–222.
Crossref
PubMed
Google Scholar
31.
Anderson RE, Tan WK, Martin HS, Meyer FB. Effects of glucose and pao2 modulation on cortical intracellular acidosis, nadh redox state, and infarction in the ischemic penumbra. Stroke. 1999; 30: 160–170.
Crossref
PubMed
Google Scholar
32.
Araki N, Greenberg JH, Sladky JT, Uematsu D, Karp A, Reivich M. The effect of hyperglycemia on intracellular calcium in stroke. J Cereb Blood Flow Metab. 1992; 12: 469–476.
Crossref
PubMed
Google Scholar
33.
Barnes PJ, Karin M. Nuclear factor-kappab: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997; 336: 1066–1071.
Crossref
PubMed
Google Scholar
34.
Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, Weih F, Frank N, Schwaninger M, Koistinaho J. Nuclear factor-kappab contributes to infarction after permanent focal ischemia. Stroke. 2004; 35: 987–991.
Crossref
PubMed
Google Scholar
35.
McInnis J, Wang C, Anastasio N, Hultman M, Ye Y, Salvemini D, Johnson KM. The role of superoxide and nuclear factor-kappab signaling in N-methyl-d-aspartate-induced necrosis and apoptosis. J Pharmacol Exp Ther. 2002; 301: 478–487.
Crossref
PubMed
Google Scholar
36.
Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M. Nf-kappab is activated and promotes cell death in focal cerebral ischemia. Nat Med. 1999; 5: 554–559.
Crossref
PubMed
Google Scholar
37.
Aljada A, Ghanim H, Mohanty P, Syed T, Bandyopadhyay A, Dandona P. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am J Clin Nutr. 2004; 80: 51–57.
Crossref
PubMed
Google Scholar
38.
Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH, Moskowitz MA. Cortical spreading depression activates and upregulates mmp-9. J Clin Invest. 2004; 113: 1447–1455.
Crossref
PubMed
Google Scholar
39.
Fukuoka S, Yeh H, Mandybur TI, Tew JM Jr. Effect of insulin on acute experimental cerebral ischemia in gerbils. Stroke. 1989; 20: 396–399.
Crossref
PubMed
Google Scholar
40.
Voll CL, Auer RN. Insulin attenuates ischemic brain damage independent of its hypoglycemic effect. J Cereb Blood Flow Metab. 1991; 11: 1006–1014.
Crossref
PubMed
Google Scholar
41.
Hamilton MG, Tranmer BI, Auer RN. Insulin reduction of cerebral infarction due to transient focal ischemia. J Neurosurg. 1995; 82: 262–268.
Crossref
PubMed
Google Scholar
42.
Zhu CZ, Auer RN. Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia. J Cereb Blood Flow Metab. 1994; 14: 237–242.
Crossref
PubMed
Google Scholar
43.
Aljada A, Ghanim H, Saadeh R, Dandona P. Insulin inhibits NFkappab and MCP-1 expression in human aortic endothelial cells. J Clin Endocrinol Metab. 2001; 86: 450–453.
PubMed
Google Scholar
44.
Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E, Ahmad S. Insulin inhibits intranuclear nuclear factor kappab and stimulates ikappab in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001; 86: 3257–3265.
PubMed
Google Scholar
45.
Aljada A, Ghanim H, Mohanty P, Kapur N, Dandona P. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (EGR)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab. 2002; 87: 1419–1422.
Crossref
PubMed
Google Scholar
46.
Ghanim H, Mohanty P, Aljada A, Chowhan S, Tripathy D, Dandona P. Insulin reduces the pro-inflammatory transcription factor, activation protein-1 (AP-1), in mononuclear cells (MNC) and plasma matrix metalloproteinase-9 (MMP-9) concentration. Diabetes. 2001; 50 (suppl 2): A408.
Google Scholar
47.
Dandona P, Aljada A, Mohanty P, Ghanim H, Bandyopadhyay A, Chaudhuri A. Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care. 2003; 26: 3310–3314.
Crossref
PubMed
Google Scholar
48.
Weis S, Shintani S, Weber A, Kirchmair R, Wood M, Cravens A, McSharry H, Iwakura A, Yoon YS, Himes N, Burstein D, Doukas J, Soll R, Losordo D, Cheresh D. Src blockade stabilizes a flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest. 2004; 113: 885–894.
Crossref
PubMed
Google Scholar
49.
Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain. 2002; 125: 2549–2557.
Crossref
PubMed
Google Scholar
50.
Mikhailidis DP, Mikhailidis AM, Barradas MA, Dandona P. Effect of nonesterified fatty acids on the stability of prostacyclin activity. Metabolism. 1983; 32: 717–721.
Crossref
PubMed
Google Scholar
51.
Chaudhuri A, Janicke D, Wilson MF, Tripathy D, Garg R, Bandyopadhyay A, Calieri J, Hoffmeyer D, Tufail S, Ghanim H, Aljada A, Dandona P. Anti-inflammatory and pro-fibrinolytic effect of insulin in acute ST-elevation myocardial infarction. Circulation. 2004; 109: 849–854.
Crossref
PubMed
Google Scholar
52.
Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab. 2000; 85: 2572–2575.
PubMed
Google Scholar
53.
Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest. 1996; 98: 894–898.
Crossref
PubMed
Google Scholar
54.
Yuan ZR, Liu B, Zhang Y, Yuan L, Muteliefu G, Lu J. Upregulated expression of neuronal nitric oxide synthase by insulin in both neurons and astrocytes. Brain Res. 2004; 1008: 1–10.
Crossref
PubMed
Google Scholar
55.
Dandona P. Endothelium, inflammation, and diabetes. Curr Diab Rep. 2002; 2: 311–315.
Crossref
PubMed
Google Scholar
56.
Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS. Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycemia: the Glucose Insulin in Stroke Trial (GIST). Stroke. 1999; 30: 793–799.
Crossref
PubMed
Google Scholar
57.
Bruno A, Saha C, Williams LS, Shankar R. IV insulin during acute cerebral infarction in diabetic patients. Neurology. 2004; 62: 1441–1442.
Crossref
PubMed
Google Scholar
58.
Gray CS, Hildreth AJ, Alberti GK, O’Connell JE. Poststroke hyperglycemia: natural history and immediate management. Stroke. 2004; 35: 122–126.
Crossref
PubMed
Google Scholar
59.
Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS. Blood pressure response to glucose potassium insulin therapy in patients with acute stroke with mild to moderate hyperglycemia. J Neurol Neurosurg Psychiatry. 2001; 70: 401–404.
Crossref
PubMed
Google Scholar
60.
Els T, Klisch J, Orszagh M, Hetzel A, Schulte-Monting J, Schumacher M, Lucking CH. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovasc Dis. 2002; 13: 89–94.
Crossref
PubMed
Google Scholar

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Sign In to Submit a Response to This Article

Information & Authors

Information

Published In

Go to Stroke
Stroke
Volume 37 • Number 1 • 1 January 2006
Pages: 267 - 273
PubMed: 16306459

Copyright

© 2006.

Versions

You are viewing the most recent version of this article.

History

Received: 21 April 2005
Revision received: 19 June 2005
Accepted: 24 June 2005
Published online: 23 November 2005
Published in print: 1 January 2006

Permissions

Request permissions for this article.

Keywords

  1. hyperglycemia
  2. insulin
  3. inflammation
  4. stroke

Authors

Affiliations

Rajesh Garg, MD
From the Division of Endocrinology, Diabetes and Metabolism (R.G., A.C., P.D.), and Department of Neurology (F.M.), State University of New York at Buffalo, New York.
View all articles by this author
Ajay Chaudhuri, MD
From the Division of Endocrinology, Diabetes and Metabolism (R.G., A.C., P.D.), and Department of Neurology (F.M.), State University of New York at Buffalo, New York.
View all articles by this author
Frederick Munschauer, MD
From the Division of Endocrinology, Diabetes and Metabolism (R.G., A.C., P.D.), and Department of Neurology (F.M.), State University of New York at Buffalo, New York.
View all articles by this author
Paresh Dandona, MD, PhD
From the Division of Endocrinology, Diabetes and Metabolism (R.G., A.C., P.D.), and Department of Neurology (F.M.), State University of New York at Buffalo, New York.
View all articles by this author

Notes

Correspondence to Paresh Dandona, MD, PhD, Director, Professor of Medicine Diabetes-Endocrinology Center of Western New York, State University of New York at Buffalo, Buffalo, 3 Gates Cir, Buffalo, NY 14209. E-mail [email protected]

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

    • Pirun Zhang,
    • Wenli Zhang,
    • Yan Han,
    • Tong Yang,
    • Jiayi Zhong,
    • Yun Han,
    • Fang Lai,
    Investigation of the connection between triglyceride-glucose (TyG) index and the risk of acute kidney injury in septic patients - a retrospective analysis utilizing the MIMIC-IV database, Renal Failure, 47, 1, (2025).https://doi.org/10.1080/0886022X.2024.2449199
    Crossref
    • Michelle P. Lin,
    • Saikrishna Vallamchetla,
    “Perfusion Scotoma” As an Imaging Marker for the No-Reflow Phenomenon After Thrombectomy?, Neurology, 103, 10, (2024).https://doi.org/10.1212/WNL.0000000000210089
    Crossref
    • Poonam Sharma,
    • Bhupesh Sharma,
    • Harsha Kharkwal,
    • Shivani Ghildiyal,
    • Vaishali M. Patil,
    Selective inhibition of T-type calcium channel preserves ischemic pre-conditioning mediated neuroprotection during cerebral ischemia reperfusion injury in diabetic mice, Metabolic Brain Disease, 40, 1, (2024).https://doi.org/10.1007/s11011-024-01470-0
    Crossref
    • Sultan Alghadeer,
    • Abdullah M. Mubarak,
    • Bashayr Alsuwayni,
    • Faisal Almurdhi,
    • Hazim Almalki,
    • Metib Alotaibi,
    The association between uncontrolled hyperglycemia (Type-2 Diabetes) and cardiovascular sequelae in patients with and without insulin, Saudi Pharmaceutical Journal, 32, 10, (102168), (2024).https://doi.org/10.1016/j.jsps.2024.102168
    Crossref
    • Ryutaro Kimura,
    • Kentaro Suzuki,
    • Tomonari Saito,
    • Takehiro Katano,
    • Yasuhiro Nishiyama,
    • Kazumi Kimura,
    Hyperglycemia and Outcomes in Patients with Successful Reperfusion by Mechanical Thrombectomy, Internal Medicine, 63, 17, (2385-2390), (2024).https://doi.org/10.2169/internalmedicine.2626-23
    Crossref
    • Chih-Hao Chen,
    • Ashkan Shoamanesh,
    • Pablo Colorado,
    • Feryal Saad,
    • Robin Lemmens,
    • Gian Marco De Marchis,
    • Valeria Caso,
    • Lizhen Xu,
    • Laura Heenan,
    • Jaime Masjuan,
    • Hanne Christensen,
    • Stuart J. Connolly,
    • Pooja Khatri,
    • Hardi Mundl,
    • Robert G. Hart,
    • Eric E. Smith,
    Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE, Stroke, 55, 6, (1477-1488), (2024)./doi/10.1161/STROKEAHA.123.045204
    Abstract
    • Yijiao Fang,
    • Bo Xiong,
    • Xue Shang,
    • Fan Yang,
    • Yuehao Yin,
    • Zhirong Sun,
    • Xin Wu,
    • Jun Zhang,
    • Yi Liu,
    Triglyceride-glucose index predicts sepsis-associated acute kidney injury and length of stay in sepsis: A MIMIC-IV cohort study, Heliyon, 10, 7, (e29257), (2024).https://doi.org/10.1016/j.heliyon.2024.e29257
    Crossref
    • Changchun Cao,
    • Tony Bowei Wang,
    • Haofei Hu,
    • Yong Han,
    • Xiaohua Zhang,
    • Yulong Wang,
    Relationship between glycated hemoglobin levels and three-month outcomes in acute ischemic stroke patients with or without diabetes: a prospective Korean cohort study, BMC Neurology, 24, 1, (2024).https://doi.org/10.1186/s12883-024-03581-8
    Crossref
    • Bing Yang,
    • Xuefang Chen,
    • Fangze Li,
    • Junrun Zhang,
    • Dawei Dong,
    • Huiyue Ou,
    • Longyan Lu,
    • Niu He,
    • Xiaohong Xu,
    • Xiufeng Xin,
    • Jingchong Lu,
    • Min Guan,
    • Hongyu Qiao,
    • Anding Xu,
    • Huili Zhu,
    Stress hyperglycemia increases short-term mortality in acute ischemic stroke patients after mechanical thrombectomy, Diabetology & Metabolic Syndrome, 16, 1, (2024).https://doi.org/10.1186/s13098-024-01272-5
    Crossref
    • Mark R. Harrigan,
    • John P. Deveikis,
    • Mark R. Harrigan,
    • John P. Deveikis,
    Ischemic Stroke, Handbook of Cerebrovascular Disease and Neurointerventional Technique, (879-963), (2024).https://doi.org/10.1007/978-3-031-45598-8_16
    Crossref
  11. See more

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/EPUB

View PDF/EPUB
Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Save for later Item saved, go to cart
Purchase Options

Purchase this article to access the full text.

Purchase access to this article for 24 hours

Hyperglycemia, Insulin, and Acute Ischemic Stroke
Stroke
  • Vol. 37
  • No. 1

Purchase access to this journal for 24 hours

Stroke
  • Vol. 37
  • No. 1
Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Figures

Tables

Media

Share

Share

Share article link

Share

View full text|Download PDF

Comment Response