Abstract
Hyperglycemia is commonly encountered in both diabetic and non-diabetic patients in acute ischemic stroke. Hyperglycemia in stroke has been associated with poor clinical outcome, a phenomenon that has been studied in experimental models, where hyperglycemia was shown to enhance cortical toxicity, increase infarct volumes, promote inflammation, and affect the cerebral vasculature. This has led to many trials attempting to modulate the hyperglycemic response as a therapeutic and neuroprotective strategy. Intensive glycemic control has been evaluated in stroke patients, with conflicting results. The evidence linking hyperglycemia with neurotoxicity coupled with the failure of intensive glucose control regimens to improve functional outcomes in stroke suggests that novel approaches should be devised. Recent attention has been paid to another related phenomenon, that of glycemic variability, which has been proven to be a predictor of outcome in critically ill patients; however, its the impact in stroke has not been evaluated.
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Introduction
Acute hyperglycemia has been consistently associated with poor clinical outcome in stroke studies, a phenomenon that had been extensively studied in experimental models, where hyperglycemia was shown to enhance cortical toxicity, increase infarct volumes, promote inflammation, and affect the cerebral vasculature [1].
Intensive glycemic control has been evaluated in stroke patients, with conflicting results. The initial enthusiasm for intensive insulin therapy (IIT) in the intensive care unit has disappeared because currently available evidence-based data fail to identify any clinical benefit at the time of continuing to outline the high risk of hypoglycemia [2].
The evidence linking hyperglycemia with neurotoxicity coupled with the failure of intensive glucose control regimens to improve functional outcomes in stroke suggests that novel approaches should be devised. Recent attention has been paid to another related phenomenon, that of glycemic variability (GV), which takes into account the constant fluctuations of glycemia, including episodes of hyper- and hypoglycemia, even in a single day [3].
Although a relatively new parameter, as well as with somewhat of a controversy surrounding its measurement, GV has proven to be a predictor of outcome independent of mean glucose levels or glycosylated hemoglobin values in critically ill patients [4]. However, the impact of GV in stroke has not been evaluated, and recent evidence suggests it could be important both as a predictor as well as a treatment goal. In this review, we will examine this evidence.
Epidemiology and Financial Burden
In 2008, after years of being the third leading cause of death in the USA, stroke dropped to the fourth. The Center for Disease Control and Prevention reports a general decline in mortality for stroke over the past half century [5]. In the USA alone, approximately 800,000 people experience a stroke every year; on average, every 40 s, someone has a stroke [6–8].
Worldwide, stroke consumes about 2–4 % of total health-care costs, and in industrialized countries, stroke accounts for more than 4 % of direct health-care costs. The total costs to society have been variously estimated at £7.6 billion in the UK at 1995 prices and Australian $1.3 billion in Australia [9, 10]. The direct and indirect cost of stroke in 2009 was $38.6 billion in USA [7].
The mean lifetime cost of ischemic stroke in the USA is estimated at $140,048, including inpatient care, rehabilitation, and follow-up cares necessary for lasting deficits [11]. The total cost of stroke from 2005 to 2050, in 2005 dollars, is projected to be $1.52 trillion for non-Hispanic whites, $313 billion for Hispanics, and $379 billion for blacks. The per capita cost of stroke estimate is highest in blacks ($25,782), followed by Hispanics ($17,201) and non-Hispanic whites ($15.597) [12].
Diabetes mellitus is a common problem whose prevalence is increasing. It is estimated that 2.8 % of the worldwide population has diabetes, a number expected to rise to 4.4 % (or around 366 million people) in 2030 [13]. Furthermore, diabetes and ischemic stroke are intimately connected. People with diabetes have more than double the risk of stroke after correction of other risk factor compared with non-diabetics, and hyperglycemia is present in 30–40 % of patients with acute ischemic stroke [14].
Diabetic and non-diabetic patients alike are worsened by hyperglycemia [15]; however, ischemic stroke patients without a history of diabetes appear most affected by high admission glucose [16]. Diabetes is estimated to be present in 10–25 % of patients with stroke, and approximately 20 % of patients with diabetes will ultimately die of stroke [17]. In non-diabetic stroke patients, up to 37 % show impaired glucose metabolism on admission, a number that rises to 58 % when reassessed at 3 months after hospitalization [18]. However, observational data likely underestimate the true prevalence of diabetes in an acute stroke cohort. It is estimated that up to half of the patients with diabetes are undiagnosed [19].
The Deleterious Effects of Hyperglycemia
Animal and human studies have confirmed that there is an association between hyperglycemia and aggravated cerebral injury after stroke (Fig. 1). Studies using transcranial Doppler imaging have demonstrated that hyperglycemia is associated with persistent occlusion in patients with ischemic stroke treated with recombinant tissue plasminogen activator (rtPa) [20], confirming preclinical evidence that shown both hyperglycemia and hyperinsulinemia decrease the activity of rtPa in animal models of ischemic stroke [21].
Mechanisms of hyperglycemia-induced neurotoxicity
Besides the effects of hyperglycemia on rtPa in human studies, it is demonstrated that hyperglycemia stimulates coagulation by increasing the production of thrombin–antithrombin complexes and by stimulating the tissue factor pathway [22, 23], whereas hyperinsulinemia decreases fibrinolytic activity by increasing the production of plasminogen activator inhibitor [24, 25].
Hyperglycemia also leads to changes in cerebral hemodynamics. Hemispheric cerebral blood flow is reduced by as much as 37 % in hyperglycemic compared with normoglycemic rats [26]. Furthermore, in a cat model of acute ischemic stroke, it was shown that hyperglycemia led to decreased penumbra blood flow after recanalization [27].
The inhibition of vasodilatation is an important mechanism by which hyperglycemia reduces cerebral blood flow. In humans, glucose infusion has been shown to reduce endothelium-dependent vasodilatation [28, 29]. Vasodilatation is predominantly mediated by endothelium-derived nitric oxide [30, 31], which is synthesized by endothelial nitric oxide synthase, whose expression is reduced with a hyperglycemic environment [32, 33].
Although restoration of blood flow to the ischemic tissue is essential for penumbral salvage, reperfusion itself can also induce injury, the phenomenon known as “ischemia–reperfusion injury” [34]. Some of the best-studied mechanisms of ischemia–reperfusion involve an intense inflammatory response and the generation of oxidative stress, and both of these mechanisms are enhanced in the setting of a hyperglycemic environment [35, 36].
Hyperglycemia increases the production of reactive oxygen species (ROS) through a protein kinase C-mediated pathway and by increasing the production of NADPH, which can lead to neuron death [37]. Hyperglycemia is known to be associated with increased expression of nuclear factor κB, known to stimulate inflammatory cytokine production, inflammatory cell function, and endothelial injury [38–40], factors ultimately resulting in increased injury and infarct size [41].
Deleterious effects of hyperglycemia over cellular homeostasis are also thought to participate in the aggravated injury response to ischemia. Hyperglycemia leads to increased lactic acid production and promotes an acidotic intracellular environment, causing mitochondrial dysfunction [42]. Support for this idea comes from a human study showing that hyperglycemia could correlate positively with increased cerebral lactate concentrations and reduced penumbral salvage after stroke [43].
Hyperglycemia in Patients With Acute Ischemic Stroke With and Without Diabetes
Glucose enters the brain microvascular endothelial cells from the blood side through GLUT1, a protein of 12 transmembrane domains that act as uniports, driving glucose down its concentration gradient [44]. Once glucose moves from the blood across the microvascular endothelial cell, it diffuses through the basal lamina and interstitial fluid to neurons, where it serves as the major cerebral energy substrate, and supports the complex metabolic interactions between neurons and astrocytes, essential for normal brain function and survival [45]. Although both hyperglycemia and hypoglycemia can affect brain function, despite variations in glucose flux (fed state, fasting state, etc.), blood glucose is maintained in a narrow range through a series of hormonal and physiological responses [46].
The best predictors of stroke recovery at 3 months are the initial neurological deficit and age; other factors include hyperglycemia, body temperature, and previous stroke [47]. Approximately a third of ischemic strokes occur in subjects with diabetes [48].
Several studies have shown that admission blood glucose is elevated in >40 % of patients with acute ischemic stroke, most commonly among patients with a history of diabetes [16, 49, 50]. A systematic review of 33 studies reported that 8–63 % of non-diabetic and 39–83 % of patients with diabetes and ischemic stroke had admission hyperglycemia [51]. Blood glucose levels seem to decline within the first 24 h after stroke onset [52], but they rise again after 24–88 h, regardless of whether the patient has diabetes mellitus [53].
A substantial proportion of patients with ischemic stroke without a documented history of diabetes have insulin resistance or diabetes at follow-up [54–57]. Furthermore, 27–37 % of patients admitted to hospital with stroke and concurrent hyperglycemia and no history of diabetes mellitus (DM) were shown to have impaired glucose tolerance 3 months after the initial stroke, and approximately one third of these cases had developed diabetes by this time point [54, 55, 57].
Serious illnesses, including stroke, are accompanied by a generalized stress reaction that involves the activation of the hypothalamic–pituitary–adrenal axis [58, 59], which leads to increased levels of serum glucocorticoids, and activation of the sympathetic autonomic nervous system [60], leading to excessive glucose production [61, 62], and insulin resistance with hyperinsulinemia [63–65].
Stroke is also associated with an increased inflammatory response and the release of cytokines [66, 67], which have been shown to activate the hypothalamic–pituitary–adrenal axis [68] and have also been associated with the development of insulin resistance [69–71].
Animals with ischemic stroke and hyperglycemia tend to have more brain edema, hemorrhagic transformation of infarcts, brain herniation, and death; the exacerbated damage with hyperglycemia is usually seen with reperfusion and occurs less with permanent occlusion [26, 38, 72–74].
Almost 30 years ago the relationship between hyperglycemia and poor clinical outcome after stroke was identified [75]; it was also demonstrated in recent studies [16, 76] and was also showed that this association is independent from other predictors of poor clinical outcome such as age, stroke severity, infarct size, or diabetic status [77–79].
A recent systematic review has revealed that hyperglycemic non-diabetic patients with ischemic stroke have an increased risk of mortality at early time points [16]. By contrast, no association between high blood glucose levels and short-term mortality was demonstrated in ischemic stroke patients with diabetes [80, 81]. In non-diabetic patients with acute ischemic stroke, hyperglycemia resulting from stroke seems to be associated with a high inhospital mortality risk and hyperglycemia that relates to a diagnosis of diabetes is not [82, 83].
Two studies have indicated that an association between hyperglycemia and poor stroke outcome exists in patients with cortical stroke, but not in patients with lacunar stroke [84, 85], and a post hoc analysis of three large clinical trials revealed that high levels of blood glucose were associated with good rather than poor clinical outcome after lacunar infarction [86].
Some studies have shown that hyperglycemia on admission to hospital also predicts poor outcome in patients with acute ischemic stroke treated with rtPa and is more pronounced than in non-rtPa-treated patients [85, 87–90]. With all this evidence, it is reasonable to expect that better control of acute hyperglycemia may improve the outcome in acute ischemic stroke patients.
Tight Glycemic Control
Aggressive correction of hyperglycemia has been studied in multiple acute illnesses in randomized trials with varied results. The most convincing trial was the surgical intensive care unit trial [91]. Patients treated aggressively had better clinical outcomes than patients under usual care. The benefits associated with aggressive hyperglycemia correction included decreased mortality, shorter time on ventilator, fewer bloodstream infections, and less critical illness polyneuropathy. A similar trial with patients in the medical intensive care unit showed less convincing results without a statistically significant difference in mortality as a primary outcome [92].
Small clinical trials have demonstrated that aggressive lowering of hyperglycemia during acute stroke is feasible and relatively safe. In one trial, glucose levels were about 30 mg/dL lower with IV insulin than with subcutaneous insulin and no serious adverse events occurred [93]. In another trial, glucose levels were 66 mg/dL lower with IV insulin than with subcutaneous insulin [94]. Patients in the aggressive treatment arm of this pilot trial had somewhat better clinical outcomes, but not statistically significant.
In the Glucose Insulin Stroke Trial—United Kingdom Trial [51], 933 acute stroke patients were randomized within 24 h after stroke onset to normal saline or insulin infusions. The mean admission glucose level was similar in the two treatment groups (137–141 mg/dL), and during treatment, the difference in mean glucose levels between the two treatment groups was only 10 mg/dL. No significant differences occurred in clinical outcomes between the two treatment groups. Four small, randomized trials were not powered to demonstrate a clinical benefit, but all showed that IIT induced a high risk of hypoglycemia in patients with acute stroke [95–98].
Despite the overwhelming evidence that hyperglycemia is statistically associated with poor functional outcome and increased mortality in patients with acute stroke, the current randomized controlled trials do not support the use of IIT. Further therapies are needed for more efficient and safer methods of improving blood glucose control.
The Deleterious Effects of Hypoglycemia
The main unwanted side effect of IIT in diabetes, hypoglycemia, is also a factor capable of aggravating cerebral ischemic injury. Even a single episode of severe hypoglycemia (<40 mg/dL or 2.2 mmol/L) or even much milder degrees of hypoglycemia (<81 mg/dL or 4.5 mmol/L) has been found to be independently associated with increased mortality in general ICU patients [99, 100].
Retinal cells have been shown to show increased susceptibility to ischemia when cultured in low-glucose mediums [101]. Cultured neurons also show increased cell death in response to ischemia when exposed to recurrent hypoglycemia in vitro [102], findings that were then confirmed in a rat model of cerebral ischemia, where recurrent hypoglycemia led to a 70 % increase in infarct size [103].
Independently of the mechanism of hypoglycemia (fasting-induced or insulin-induced), brain cells subjected to ischemia in these conditions show impaired energy metabolism and increased exposure to oxidative stress [104]. Besides oxidative stress, other mechanisms implicated in hypoglycemia-induced neurotoxicity during ischemia include mitochondrial dysfunction and increased calcium influx, but the precise pathways involved remain to be elucidated [105].
Considering the accumulating evidence showing that episodes of hypoglycemia in the context of intensive glucose-lowering therapy in critically ill patients are associated with increased mortality [99, 100, 106], the implementation of such strategies should be carefully considered and great care taken to avoid episodes of hypoglycemia.
The fact that both hyperglycemia and hypoglycemia can aggravate brain injury after stroke could partly explain the negative results of IIT trials but, importantly, also highly suggests that other more dynamic measures of glycemic control, such as GV, could more accurately predict outcome and be a suitable therapeutic objective.
Glycemic Variability
Oxidative stress, the putative mediator of diabetes complications [107], has been reported to be greater for intermittent as opposed to sustained hyperglycemia under experimental conditions [108] with confirmation in clinical studies [109, 110]. The potential role for GV in DM complications appears, therefore, to be an open question.
The Diabetes Control and Complications Trial (DCCT) demonstrated that lowering A1C significantly reduces the incidence and progression of microvascular complications in type 1 diabetes. A comparison of patients in both groups with identical A1C levels shows significant differences, as an example the risk of retinopathy in control patients with an A1C of 9 % was approximately 2.5 times greater than the risk of experimental patients with a 9 % A1C [111].
The only significant difference between these groups is that almost all patients of the control group were on twice daily NPH insulin, whereas subjects in the experimental group were on basal-bolus therapy or an insulin pump. This analysis of the data strongly suggests that the findings relate more to the impact of GV rather than to absolute A1C value [112].
A consensus on the gold standard method to measure glucose variability in clinical practice and research is still lacking, although a number of indicators have been proposed. The easiest way to get an impression of the GV in an individual patient is to calculate the standard deviation (SD) of plasma glucose measurements and/or the coefficient of variation (CV), if one wishes to correct for the mean [113].
A prospective observational study in 100 type 1 diabetes patients confirmed no relationship between short-term GV measured as SD and microvascular complications [114]. However, they found that GV was significantly related to the presence of peripheral neuropathy and was a borderline predictor of its incidence (hazard ratio, 1.73; P = 0.07), suggesting that the nervous system may be vulnerable to GV.
Three retrospective studies analyzed GV as a predictor of mortality at the adult ICU [115–117] concluding that GV, measured as SD, was a significant predictor of mortality independently from the severity of illness. A subgroup analysis of patients with diabetes displayed no relation with survival in contrast to patients without diabetes [116]. These results may suggest that patients with diabetes “get accustomed” to fluctuating glucose levels, making them less devastating.
A retrospective study of 935 patients showed that an increased GV, assessed by the SD and CV, is independently associated with longer length of stay and greater 90-day mortality in non-critically ill patients. These associations were independent of age, race, service of care, previous diagnosis of diabetes, A1C, body mass index, the use of regular insulin, mean plasma glucose, and hypoglycemia [118].
In the neurocritical care setting, a study showed that in patients with traumatic brain injury, GV, defined by SD and percentage of excursion from the preset range glucose level, was significantly associated with poorer long-term functional outcome [119] (Table 1).
Conclusions and Future Considerations
Exenatide, a glucagon-like peptide-1 (GLP-1) agonist, has shown in clinical studies that could minimize the risk for GV to a greater degree than insulin glargine or glimepiride treatment, even with identical average glucose levels [120, 121]. Exenatide has been shown to be neuroprotective in animal models of acute ischemic stroke. Both diabetic and non-diabetic exenatide-treated animals showed reduced infarct volume, reduced oxidative stress, inflammation, and apoptosis after ischemic stroke, an effect partially mediated trough reduced intracellular levels of cAMP and the protein kinase A pathway [122–125].
A study has shown that the addition of a dipeptidyl peptidase (DPP)-4 inhibitor to metformin therapy in diabetic patients significantly reduced GV, albeit mostly trough a reduction in basal hyperglycemia [126]. DPP-4 inhibitor administration to diabetic and non-diabetic rats led to reduced infarct volumes in models of transient middle cerebral artery occlusion, in a glucose-independent pathway likely involving GLP-1 and brain-derived growth factor production [127, 128].
Ultra-long-acting and high-strength formulations of new basal insulin analogs like insulin degludec, which differs from human insulin by deletion of threonine at position B30 and the attachment of a 16-carbon fatty diacid to the lysine residue at position B29 via a gamma-glutamic acid spacer [129], PEGylated Lispro, insulin lispro that has been site-specifically PEGylated with 20-kDa moiety at lysine B28, via a urethane bond [130], and glargine U300, a new formulation containing glargine at a concentration of 300 U/mL rather than the usual 100 U/mL [131], have the potential for less glycemic variability, less (nocturnal) hypoglycemia, and greater weight loss [132–134].
Despite there is no consensus on how to measure the GV, it is being demonstrated that an increase in this parameter leads to worse outcomes in many clinical settings. In stroke patients, the worst outcomes associated with hyperglycemia and the lack of benefit from IIT must be followed to a search for better ways to manage hyperglycemia. There are some strategies that are associated with an improvement in GV, and these strategies, in some animal models, have a neuroprotective role in stroke.
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González-Moreno, E.I., Cámara-Lemarroy, C.R., González-González, J.G. et al. Glycemic Variability and Acute Ischemic Stroke: The Missing Link?. Transl. Stroke Res. 5, 638–646 (2014). https://doi.org/10.1007/s12975-014-0365-7
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DOI: https://doi.org/10.1007/s12975-014-0365-7