How Does Hyperglycemia Affect The Ischemic Brain

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Although an accumulating number of studies have convincingly demonstrated an association between hyperglycemia and poor outcome after stroke, it remains controversial whether this association is causal, i.e., hyper-glycemia is actually causing poor outcome.

Hyperglycemia could also be epiphenomenal to a more pronounced stress reaction with higher levels of blood glucose in more severe stroke. Indeed, higher levels of glucose have been associated with more severe stroke (7, 7375). On the other hand, most [but not all (30, 76, 77)] studies showed that the deleterious effect of hyperglycemia is independent of clinical severity (7, 13, 53, 75, 76).

Several (mainly experimental) studies and observations from imaging studies have provided clues as to how impaired glucose metabolism resulting in hyperglycemia and insulin resistance could be detrimental to the ischemic brain. In this context, it is important to realize that the sequence of reactions that occur after arterial occlusion, leading to ischemia and ultimately to infarction, is complex and dynamic and will likely differ from patient to patient, depending among other factors on age, gender, and cardiovascular history. A dynamic interplay of multiple reactions will occur concomitantly over time and it is unlikely that any of these processes can be seen as the sole or dominant cause leading to infarction.

In the brain, glucose is transported via the glucose transporters (GLUT-1-3). These insulin independent transporters continuously transport glucose, leading to intracellular glucose accumulation when plasma glucose levels are high (78). Hyperglycemia, both acute and chronic, can in turn induce a variety of biochemical changes and is believed to form the basis for many biochemical alterations involved in diabetic complications (79).

In the following paragraphs we will outline the mechanisms thought to be responsible for acute hyperglycemia to be detrimental for the ischemic brain. These mechanisms involve impaired recanalization, impaired (re)perfusion, reperfusion injury, and direct detrimental effects of glucose (see also Fig. 1B).

Impaired Recanalization

As mentioned earlier, it was observed from clinical studies that hyper-glycemia is capable of counterbalancing the beneficial effect of rt-PA treatment (14, 54). This observation is supported by the results of a study that used Transcranial Doppler (TCD) imaging to assess rt-PA-induced recanal-ization in patients with middle cerebral artery occlusion. It was demonstrated that glucose levels exceeding 8.8 mmol/L were associated with a persistent occlusion [OR: 7.3 (95%CI) 1.3-42.3], suggesting that hyperglycemia hampers recanalization (80). An explanation for this can be found in experimental studies that report a relation between an abnormal glucose metabolism and abnormal hemostasis. In these studies, hyperglycemia was shown to stimulate coagulation by increasing thrombin-antithrombin complexes and the tissue factor pathway (81-84), and hyperinsulinemia was shown to decrease fibrinolytic activity by increasing plasminogen activator inhibitor (PAI) (81, 85-87). Furthermore, both hyperglycemia and hyperinsulinemia have been shown to decrease the activity of rt-PA itself (85). These observations support the hypothesis that an altered glucose metabolism impairs recanalization, probably due to increased coagulation and decreased fibri-nolytic activity.

Interestingly, the detrimental effects of hyperglycemia were shown to be more pronounced in patients with early recanalization than in patients with delayed or no recanalization (55). This suggests that hyperglycemia is also harmful more downstream of the occlusion and prevents the reperfusion of the penumbra.

Decreased Perfusion

Reperfusion of ischemic tissue is critical for penumbral salvage. In experimental stroke, hyperglycemia is associated with decreased reperfusion resulting in increased infarct volumes when compared to normoglycemic controls (88-91). Cerebral blood flow (CBF) was reduced by 37% in hyperglycemic compared to normoglycemic rats (89). After recanalization, penumbral blood flow was 60% of pre-ischemic values in hyperglycemic, vs. 89% in normoglycemic conditions (92).

An important mechanism by which hyperglycemia appears to reduce CBF is by decreasing vasodilatation, which is necessary for optimal reperfusion. For example, glucose infusion for 6 h was shown to reduce endothelium-dependent vasodilatation in healthy humans (93, 94).

Vasodilatation is predominantly mediated by endothelium-derived nitric oxide (NO) which is synthesized by endothelial NO synthetase (eNOS) (95, 96). Reduction of eNOS gene expression has been reported in endothelial cells in a hyperglycemic environment (97, 98), probably by reducing protein kinase C (PKC) (99). Moreover, hyperglycemia can reduce the production of NO by increasing the activity of nicotinamide adenine dinu-cleotide phosphate (NADPH)-oxidase, also through the activation of PKC (100). NADPH-oxidase in turn can reduce eNOS activity and, additionally, increases superoxide that neutralizes NO with the formation of peroxynitrite (101,102).

Besides reduced vasodilatation via the reduction of NO, hyperglycemia is also implicated in several signaling pathways involved in vascular function. Hyperglycemia stimulates the lipo-oxygenase and cyclo-oxygenase pathways, leading to enhanced formation of vasoconstrictive prostaglandins such as thromboxane A2 (103, 104). Additionally, hyperglycemia can also alter the eicosanoid production affecting vascular tone resulting in vasoconstriction (105).

Exacerbation of Reperfusion Injury

Although restoration of the blood flow to the ischemic tissue is essential for penumbral salvage, reperfusion itself can also induce injury. Hyperglycemia is associated with an exacerbation of this so-called reperfusion injury. The mechanisms by which reperfusion causes injury to the ischemic brain are complex and fall beyond the scope of this chapter. Here, we will only (briefly) consider the most important mechanisms where acute hyper-glycemia appears to be involved. The more interested reader is referred to more specialized reviews on this topic (79,106,107).

The hallmarks of reperfusion injury are oxidative stress and inflammation, and both these processes appear to be influenced by hyperglycemia. Oxidative stress is mainly caused by an imbalance between the production and neutralization of reactive oxygen species (ROS), such as superoxide and peroxides. These ROS have been shown to damage various components of the cell, including proteins, lipids, mitochondrial function, and DNA, which leads to an impaired blood-brain barrier (BBB) function, edema formation, and increased infarct volume (106,108-110).

Hyperglycemia increases the production of ROS through the activation of PKC, and through increased NADH production, and is as such associated with increased oxidative stress. In fact, increased oxidative stress by the formation of superoxide is considered one of the major pathways leading to hyperglycemic complications (79).

Closely (inter)related to oxidative stress in the context of reperfusion injury is the inflammatory response (106, 111). During ischemia the inflammatory response develops through the activation of pro-inflammatory cytokines (e.g., TNFa, interleukins, and cell adhesion molecules) and by the infiltration of inflammatory cells (e.g., leukocytes and macrophages). Inflammation can cause molecular and biochemical modifications resulting in tissue injury and increased infarction. Additionally, inflammation is a significant source of oxidative stress (106,107).

Hyperglycemia is shown to increase several pro-inflammatory transcription factors involved in inflammation, prominently nuclear factor KB(kappa beta), which plays a key role in the regulation of the inflammatory responses by enhancing pro-inflammatory cytokines and by promoting the adhesion of inflammatory cells (106,107,111).

Other Mechanisms

Hyperglycemia has also been associated with several other mechanisms of tissue injury after infarction. Although controversial (112), one of the most propagated ideas is that anaerobic glycolysis under hyperglycemic conditions is associated with the accumulation of lactic acid and a derangement in pH homeostasis which can in turn contribute to increased brain injury (113-115). In humans, this hypothesis was supported by the previously mentioned observation that hyperglycemia correlates with greater lactate production and reduced penumbral salvage after infarction (71) (Fig. 3). Additionally, hyperglycemia may also directly affect mitochondrial function in the ischemic penumbra and cause significant intracellular acidosis (115).

More recently, hyperglycemia has been associated with an increased rate of hemorrhagic complications after rt-PA treatment. In the National Institutes of Neurological Disorders and Stroke (NINDS) trial that investigated the effect of rt-PA treatment, a statistical trend was seen for severe hyper-glycemia (>16.7mmol/L) as a predictor of symptomatic hemorrhage (116). In another study, hyperglycemia (>11.1 mmol/L) was associated with a 25% symptomatic hemorrhage rate and the odds ratio (OR) on symptomatic hemorrhage associated with each 5.5 mmol/L increment of admission glucose was 2.3 (95%CI: 1.1-4.8) (57). These observations were later confirmed by two other studies (57, 59). In all of these studies, however, DM was also associated with an increased rate of hemorrhage and hyperglycemia may therefore only be a marker of DM, which in turn has been associated with impairments of the blood-brain barrier and microvasculature that may result in an increased bleeding risk (57,117).

Taken together, hyperglycemia appears to be implicated on various levels in the dynamic reactions involved in cerebral infarction, ultimately leading to impaired penumbral salvage and increased infarct size. It is important, however, to realize that part of the evidence comes from experimental in vitro or animal studies which are an imperfect representation of human stroke. While stroke in humans is a very heterogeneous disease, with great variability in etiology, location, and severity, experimental models are usually performed in healthy young animals, comparable of equal age and gender and under standardized circumstances. Extrapolation to the situation in humans must therefore be done with great caution.

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