Poststroke Hyperglycemia Research Articles

Stroke Prevention and Treatment in People With Type 2 Diabetes: Is There a Role for GLP-1 (Glucagon-Like Peptide-1) Analogues?

Stroke is a leading cause of disability and death, and people with type 2 diabetes (T2D) have a greater risk of stroke and death or disability from stroke. The underlying pathophysiology associating stroke and T2D is complicated by the association of risk factors for stroke frequently seen in people with T2D. Treatments to reduce the excess risk of new-onset stroke or to improve outcomes in people with T2D following stroke would be of major clinical interest. In practice, the focus of care in people with T2D remains treating risk factors for stroke, such as lifestyle and pharmacological interventions for hypertension, dyslipidemia, obesity, and glycemic control. More recently, cardiovascular outcome trials primarily designed to assess the cardiovascular safety of GLP-1RAs (glucagon-like peptide-1 receptor analogues) have consistently observed a reduced stroke risk in people with T2D. This is supported by several meta-analyses of cardiovascular outcome trials observing clinically important risk reductions in stroke. Moreover, phase II trials have described reductions in poststroke hyperglycemia in people with acute ischemic stroke suggestive of improved outcomes following admission to hospital with acute stroke. In this review, we discuss the increased risk of stroke in people with T2D and outline the key associated mechanisms responsible. We discuss the evidence from cardiovascular outcome trials exploring GLP-1RA use and highlight areas of potential interest for future work in this rapidly developing area of clinical research.

Abstract WP235: Hyperglycemia In The Days After Stroke Exacerbates Brain Injury By Increasing Microglial Superoxide Production

It has been recognized for decades that elevated blood glucose (hyperglycemia) during ischemia/reperfusion greatly exacerbates injury; however, little is known about the effect of hyperglycemia that begins later, over the hours to days after ischemia. This often occurs after stroke as part of a systemic stress response, even in non-diabetic patients, but neither clinical evidence nor prior basic science studies provide guidance on how post-stroke hyperglycemia should be managed. Here we investigated this issue using a mouse photothrombotic model of permanent ischemia. Normoglycemia or hyperglycemia (blood glucose of 300-400 mg/dL; 15-20 mM) was maintained between 17 - 48 hours after ischemia onset. Post-stroke hyperglycemia was found to increase the final infarct volume, increase hemorrhage formation, and exacerbate motor dysfunction. Hyperglycemia also increased superoxide formation in peri-lesional microglia/macrophages. Importantly, hyperglycemia did not have these deleterious effects in p47 phox-/- mice, which cannot form an active superoxide-producing NADPH oxidase-2 complex, or in wild-type mice treated with a peptide inhibitor of NADPH oxidase-2 (gp91-TAT peptide). These results suggest that hyperglycemia occurring many hours after ischemia can increase oxidative stress in peri-infarct tissues by fueling NADPH oxidase activity in reactive microglia/macrophages, and by this mechanism may contribute to worsened outcome.

Mini review

The impact of stroke, currently the second leading cause of death worldwide, continues to worsen, and even those that survive can have persistent neurological deficits. A potentially significant implication may be due to hyperglycemia, found in one-third of all acute ischemic stroke (AIS) patients. However, prior studies reported conflicting information about the impact of hyperglycemia on poststroke prognosis, likely due to different measurements of stress-induced hyperglycemia. The glucose-to-glycated hemoglobin ratio is an index of stress-induced hyperglycemia after AIS that better quantifies acute changes in blood glucose, as opposed to absolute variations in glucose levels. Moderate blood glucose reductions might counteract the negative effects of hyperglycemia and glycemic control medications can also play a role in neuroprotection. The liver is the main organ that functions to maintain energy and glucose metabolism and the effects of AIS can reach far peripheral organs, including the liver. In this review, we highlighted the mechanism responsible for acute poststroke hyperglycemia, a hepatic inflammatory pathway that results in hepatic gluconeogenesis and reduced hepatic insulin sensitivity. Hepatitis cascades lead to hepatic gluconeogenesis, and targeted therapy with antihyperglycemic drugs has the potential to improve stroke prognosis and recovery.

Abstract TP235: Delayed FGF21 Administration Improves Cerebrovascular Remodeling And White Matter Repair After Focal Stroke In Diabetic Mice

Introduction: Type 2 diabetes mellitus (T2DM) is a major comorbidity exacerbating ischemic brain injury and impairing post-stroke recovery. Our previous study suggested that recombinant human fibroblast growth factor (rFGF) 21 might be a potent therapeutic targeting multiple aspects of pathophysiology in T2DM stroke. As a continuation of our previous work investigating the therapeutic effects of rFGF21 in T2DM stroke, this study aims to evaluate the potential effects of rFGF21 on cerebrovascular remodeling during a delayed phase after T2DM stroke. Methods: Permanent distal middle cerebral artery occlusion was performed in heterozygous non-diabetic db/+ and homozygous diabetic db/db mice. Daily rFGF21 administration was initiated one week after stroke induction and maintained for up to two weeks thereafter. Multiple markers associated with post-stroke recovery, including angiogenesis, oligodendrogenesis, white matter integrity and neurogenesis, were assessed up to three weeks after stroke. Results: Our results showed an impairment in post-stroke vascular remodeling under T2DM condition, reflected by the decreased expression of trophic factors in brain microvessels and impairments of angiogenesis. The defected cerebrovascular remodeling was accompanied by the decreased oligodendrogenesis and neurogenesis. However, delayed rFGF21 administration normalized post-stroke hyperglycemia and improved neurological outcomes, which may partially via the promotion of pro-angiogenic trophic factor expression in brain microvessels and cerebrovascular remodeling. The better cerebrovascular remodeling may also contribute to oligodendrogenesis, white matter integrity and neurogenesis after T2DM stroke. Conclusion: Delayed rFGF21 administration may improve neurological outcomes in T2DM stroke mice, at least in part by normalizing the metabolic abnormalities and promoting cerebrovascular remodeling and white matter repair.

Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis.

Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community.

Jak2 Inhibitor AG490 Improved Poststroke Central and Peripheral Inflammation and Metabolic Abnormalities in a Rat Model of Ischemic Stroke.

Poststroke hyperglycemia and inflammation have been implicated in the pathogenesis of stroke. Janus Kinase 2 (Jak2), a catalytic signaling component for cytokine receptors such as Interleukin-6 (IL-6), has inflammatory and metabolic properties. This study aimed to investigate the roles of Jak2 in poststroke inflammation and metabolic abnormality in a rat model of permanent cerebral ischemia. Pretreatment with Jak2 inhibitor AG490 ameliorated neurological deficit, brain infarction, edema, oxidative stress, inflammation, caspase-3 activation, and Zonula Occludens-1 (ZO-1) reduction. Moreover, in injured cortical tissues, Tumor Necrosis Factor-α, IL-1β, and IL-6 levels were reduced with concurrent decreased NF-κB p65 phosphorylation, Signal Transducers and Activators of Transcription 3 phosphorylation, Ubiquitin Protein Ligase E3 Component N-Recognin 1 expression, and Matrix Metalloproteinase activity. In the in vitro study on bEnd.3 endothelial cells, AG490 diminished IL-6-induced endothelial barrier disruption by decreasing ZO-1 decline. Metabolically, administration of AG490 lowered fasting glucose, with improvements in glucose intolerance, plasma-free fatty acids, and plasma C Reactive Proteins. In conclusion, AG490 improved the inflammation and oxidative stress of neuronal, hepatic, and muscle tissues of stroke rats as well as impairing insulin signaling in the liver and skeletal muscles. Therefore, Jak2 blockades may have benefits for combating poststroke central and peripheral inflammation, and metabolic abnormalities.

Alleviation of Neuronal Cell Death and Memory Deficit with Chungkookjang Made with Bacillus amyloliquefaciens and Bacillus subtilis Potentially through Promoting Gut-Brain Axis in Artery-Occluded Gerbils.

Short-term fermented soybeans (chungkookjang) with specific Bacillus (B.) spp. have anti-obesity, antidiabetic, and anti-stroke functions. We examined the hypothesis that the long-term consumption of B. amyloliquefaciens SCGB 1 fermented (CKJ1) and B. subtilis SCDB 291 (CKJ291) chungkookjang can alleviate clinical symptoms and hyperglycemia after ischemic stroke by promoting the gut microbiota–brain axis. We examined this hypothesis in Mongolian male gerbils with stroke symptoms induced by carotid artery occlusion. The artery-occluded gerbils were divided into five groups: no supplementation (Control, Normal-control), 4% cooked soybeans (CSB), CKJ1, or CKJ291 in a high-fat diet for 3 weeks. The carotid arteries of gerbils in the Control, CSB, CKJ1, and CKJ291 groups were occluded for 8 min and they then continued on their assigned diets for an additional 3 weeks. Normal-control gerbils had no artery occlusion. The diets in all groups contained an identical macronutrient composition using starch, casein, soybean oil, and dietary fiber. The CSB, CKJ1, and CKJ291 groups exhibited less neuronal cell death than the Control group, while the CKJ1 group produced the most significant reduction among all groups, as much as 85% of the Normal-control group. CKJ1 and CKJ291 increased the blood flow and removal of blood clots, as determined by Doppler, more than the Control. They also showed more improvement in neurological disorders from ischemic stroke. Their improvement showed a similar tendency as neuronal cell death. CKJ1 treatment improved memory impairment, measured with Y maze and passive avoidance tests, similar to the Normal-control. The gerbils in the Control group had post-stroke hyperglycemia due to decreased insulin sensitivity and β-cell function and mass; the CKJ291, CSB, and CKJ1 treatments protected against glucose disturbance after artery occlusion and were similar to the Normal-control. CKJ1 and CKJ291 also reduced serum tumor necrosis factor-α concentrations and hippocampal interleukin-1β expression levels, compared to the Control. CKJ1 and CKJ291 increased the contents of Lactobacillus, Bacillus, and Akkermansia in the cecum feces, similar to the Normal-control. Picrust2 analysis showed that CKJ1 and CKJ291 increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced the lipopolysaccharide biosynthesis and fatty acid metabolism compared to the Control. In conclusion, daily CKJ1 and CKJ291 intake prevented neuronal cell death and memory dysfunction from the artery occlusion by increasing blood flow and β-cell survival and reducing post-stroke-hyperglycemia through modulating the gut microbiome composition and metabolites to influence the host metabolism, especially inflammation and insulin resistance, protecting against neuronal cell death and brain dysfunction. CKJ1 had better effects than CKJ291.

Post-stroke Hyperglycemia in Non-diabetic Ischemic Stroke is Related With Worse Functional Outcome: A Cohort Study.

ObjectiveTo investigate long-term and serial functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.MethodsThe Korean Stroke Cohort for Functioning and Rehabilitation (KOSCO) is a large, multi-center, prospective cohort study of stroke patients admitted to participating hospitals in nine areas of Korea. From KOSCO, ischemic stroke patients without diabetes were recruited and divided into two groups: patients without diabetes without (n=779) and with post-stroke hyperglycemia (n=223). Post-stroke hyperglycemia was defined as a glucose level >8 mmol/L. Functional assessments were performed 7 days and 3, 6, and 12 months after stroke onset.ResultsThere were no significant differences in baseline characteristics between the groups, except in the age of onset and smoking. Analysis of the linear correlation between the initial National Institutes of Health Stroke Scale (NIHSS) score and glucose level showed no significant difference. Among our functional assessments, NIHSS, Fugl-Meyer Assessment (affected side), Functional Ambulatory Category, modified Rankin Scale, and Korean Mini-Mental State Examination (K-MMSE) showed statistically significant improvements in each group. All functional improvements except K-MMSE were significantly higher in patients without post-stroke hyperglycemia at 7 days and 3, 6, and 12 months.ConclusionThe glucose level of ischemic stroke patients without diabetes had no significant correlation with the initial NIHSS score. The long-term effects of stress hyperglycemia showed worse functional outcomes in ischemic stroke patients without diabetes with post-stroke hyperglycemia.

Delayed rFGF21 Administration Improves Cerebrovascular Remodeling and White Matter Repair After Focal Stroke in Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is a major comorbidity exacerbating ischemic brain injury and impairing post-stroke recovery. Our previous study suggested that recombinant human fibroblast growth factor (rFGF) 21 might be a potent therapeutic targeting multiple aspects of pathophysiology in T2DM stroke. This study aims to evaluate the potential effects of rFGF21 on cerebrovascular remodeling after T2DM stroke. Permanent distal middle cerebral artery occlusion was performed in heterozygous non-diabetic db/ + and homozygous diabetic db/db mice. Daily rFGF21 administration was initiated 1week after stroke induction and maintained for up to 2weeks thereafter. Multiple markers associated with post-stroke recovery, including angiogenesis, oligodendrogenesis, white matter integrity, and neurogenesis, were assessed up to 3weeks after stroke. Our results showed an impairment in post-stroke vascular remodeling under T2DM condition, reflected by the decreased expression of trophic factors in brain microvessels and impairments of angiogenesis. The defected cerebrovascular remodeling was accompanied by the decreased oligodendrogenesis and neurogenesis. However, delayed rFGF21 administration normalized post-stroke hyperglycemia and improved neurological outcomes, which may partially be via the promotion of pro-angiogenic trophic factor expression in brain microvessels and cerebrovascular remodeling. The better cerebrovascular remodeling may also contribute to oligodendrogenesis, white matter integrity, and neurogenesis after T2DM stroke. Therefore, delayed rFGF21 administration may improve neurological outcomes in T2DM stroke mice, at least in part by normalizing the metabolic abnormalities and promoting cerebrovascular remodeling and white matter repair.

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity.

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin (including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies.

Effects of Glycemic Gap on Post-Stroke Cognitive Impairment in Acute Ischemic Stroke Patients.

Background: Post-stroke hyperglycemia is a frequent finding in acute ischemic stroke patients and is associated with poor functional and cognitive outcomes. However, it is unclear as to whether the glycemic gap between the admission glucose and HbA1c-derived estimated average glucose (eAG) is associated with post-stroke cognitive impairment (PSCI). Methods: We enrolled acute ischemic stroke patients whose cognitive functions were evaluated three months after a stroke using the Korean version of the vascular cognitive impairment harmonization standards neuropsychological protocol (K-VCIHS-NP). The development of PSCI was defined as having z-scores of less than −2 standard deviations in at least one cognitive domain. The participants were categorized into three groups according to the glycemic gap status: non-elevated (initial glucose − eAG ≤ 0 mg/dL), mildly elevated (0 mg/dL < initial glucose − eAG < 50 mg/dL), and severely elevated (50 mg/dL ≤ initial glucose − eAG). Results: A total of 301 patients were enrolled. The mean age was 63.1 years, and the median National Institute of Health Stroke Scale (NIHSS) score was two (IQR: 1–4). In total, 65 patients (21.6%) developed PSCI. In multiple logistic regression analyses, the severely elevated glycemic gap was a significant predictor for PSCI after adjusting for age, sex, education level, initial stroke severity, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and left hemispheric lesion (aOR: 3.65, p-value = 0.001). Patients in the severely elevated glycemic gap group showed significantly worse performance in the frontal and memory domains. Conclusions: In conclusion, our study demonstrated that an elevated glycemic gap was significantly associated with PSCI three months after a stroke, with preferential involvement of frontal and memory domain dysfunctions.

Personalized Consideration of Admission-Glucose Gap between Estimated Average and Initial Glucose Levels on Short-Term Stroke Outcome.

Background: Poststroke hyperglycemia is associated with poor outcomes. Most prior studies used initial glucose as an indicator of poststroke hyperglycemia without considering glycemic control status at the time of stroke occurrence. We aimed to investigate the effect of an admission-glucose gap on short-term functional outcomes in acute ischemic stroke (AIS). Methods: We enrolled patients with AIS or transient ischemic attack who had been admitted within 7 days of symptom onset to three stroke centers from May 2016 to December 2019. The admission-glucose gap between estimated average glucose levels (eAG) and initial glucose level (eAG–initial glucose) was categorized into four groups. The short-term functional outcome was evaluated using the modified Rankin Scale (mRS) score at 3 months after stroke onset and was dichotomized. Results: Among 1332 included subjects, 548 (41.1%) had poor short-term functional outcomes. After adjusting for multiple variables, a severe negative glucose gap (eAG–initial glucose ≤ −50 mg/dL) was significantly associated with poor short-term functional outcome (OR, 1.573; 95% CI, 1.101–2.248). After dichotomizing glycemic control status, its significance was only maintained in the good glycemic control group (HbA1c < 6.5%) (OR, 1.914; 95% CI, 1.155–3.169). Conclusions: An elevated admission-glucose gap, in which the initial glucose level was much higher than the estimated glucose level was based on HbA1c, was associated with poor stroke prognosis. In addition to admission-glucose levels, glycemic control status at the time of stroke onset should be considered when predicting short-term stroke outcomes.

HYPERGLYCEMIC CRISIS FUNCTIONING AS HYPEROSMOTIC RESCUE IN A PATIENT WITH ISCHEMIC CEREBELLAR STROKE

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Cerebral injury is a rare complication of hyperglycemic crisis, typically occurring within 3-12 hours of treatment initiation. It is presumed to be a result of aggressive fluid resuscitation and rapid serum osmolality changes following initiation of insulin therapy. Incidence is less than 1% in children with only limited cases reported in adults. We report a rare case of hyperglycemic hyperosmolar state (HHS) secondary to acute pancreatitis and methamphetamine abuse in a patient with concomitant ischemic cerebellar infarct who rapidly deteriorated following corrective therapy. We propose a potential pathophysiological explanation of her presentation, highlighting the challenges in management. CASE PRESENTATION: A 54-year-old female with poorly controlled type-2 diabetes mellitus (DM) noncompliant with insulin therapy, hypertension, and methamphetamine abuse presented with acute encephalopathy and gastrointestinal distress. She was hypertensive and tachycardic on arrival in no respiratory distress. Labs were significant for profound hyperglycemia with blood glucose of 912 mg/dL, bicarbonate 19.5 mmol/L, anion gap 24 mmol/L, beta-hydroxybutyrate of 0.98 mmol/L, lactate 9.2 mmol/L, lipase 2462 U/L, and balanced electrolytes. Toxicology screen was positive for methamphetamine. ABG on room air showed normal range pH. CT head revealed a 2.6 cm region of hypoattenuation in the inferior cerebellum suggestive of acute ischemic infarct. She was given IV fluid followed by insulin infusion and admitted to the ICU. Shortly after, she became rapidly hypoxemic with bradypnea requiring rapid sequence intubation, followed by sudden bradycardia and ultimately fatal PEA arrest. DISCUSSION: To our knowledge, there has never been a reported case of concomitant HHS and acute cerebral ischemia in adults. Although MRI was unable to be performed, we suspect our patient suffered rapid intracranial pressure elevation as evidenced by development of Cushing triad. Patients with ischemic cerebellar infarcts are at high risk for reactive cerebral edema. Glucose is a natural osmotic agent, increasing serum tonicity, and may have provided an ironic therapeutic benefit. Rapid correction of her hyperosmolar state with insulin therapy in conjunction with aggressive fluid resuscitation, likely precipitated sudden intracellular fluid influx and subsequent herniation. Post-stroke hyperglycemia is a common physiological occurrence and may have served as a potential hyperosmotic rescue measure in our patient. CONCLUSIONS: Cerebral edema is a rare but potentially fatal complication of hyperglycemic crisis therapy. Risk is significantly elevated in those with acute ischemic infarcts and careful correction of glucose and electrolytes should be attempted. Reference #1: Varela D, Held N, Linas S. Overview of Cerebral Edema During Correction of Hyperglycemic Crises. Am J Case Rep. 2018;19:562-566. DISCLOSURES: No relevant relationships by Helen Li Mitchell, source=Web Response No relevant relationships by Sushant Soni, source=Web Response No relevant relationships by Shawnt Tosonian, source=Web Response No relevant relationships by Nathaniel Wise, source=Web Response No relevant relationships by Tommy Zaharakis, source=Web Response

The peripheral immune response in hyperglycemic stroke

ObjectivesHyperglycemia is common in acute ischemic stroke patients and is associated with poor clinical outcome. However, aggressive reduction of post-stroke hyperglycemia did not improve clinical outcome, suggesting that other mechanisms are playing a detrimental role in hyperglycemic stroke. We hypothesize that the acute post-stroke immune response is altered in the hyperglycemic state leading to higher mortality and morbidity. The objective of this study was to characterize temporal changes in circulating immune cells after stroke and their association with clinical outcomes in hyperglycemic compared to euglycemic patients. Patients and methodsThis retrospective study included 97 (58 % euglycemic, 42 % hyperglycemic) patients presenting within 12 h of symptom onset of stroke. Blood neutrophil, monocyte and lymphocyte concentrations were measured sequentially for 96 h post stroke. Primary clinical outcome was the difference in the NIH stroke scale at admission compared to discharge. Secondary outcome measures included discharge disposition and the modified Rankin Scale (mRS) at 90 days. ResultsCirculating neutrophils were significantly higher in hyperglycemic than in euglycemic patients within the first 48 h post stroke, while lymphocyte counts trended to be lower. Hyperglycemic patients had higher mortality rates, less favorable discharge disposition and worse neurological function at 90 days. In both groups, the neutrophil to lymphocytes ratio ((NLR) remained strongly associated with neurological function at discharge within the first 24 h (p < 0.001), and remained significant in hyperglycemic patients up to 48 h (p < 0.001). Multivariate regression analysis showed no confounding by other factors and a significant correlation with differences in NIHSS score (CI; - 9.287 to -1.46, p = 0.0077**) and NLR (CL; 0.6058–6.901, p = 0.0203*) in hyperglycemic patients. ConclusionsOur data suggests that circulating immune cells play an important role in mediating poor clinical outcome in hyperglycemic patients following stroke. The NLR is a strong predictor of neurological outcomes in hyperglycemic patients. Thus, the modulation of immune cells may be a viable therapeutic approach to improve outcomes for this high risk group.

Association of pre- and post-stroke glycemic status with clinical outcome in spontaneous intracerebral hemorrhage

In this study, we aimed to disclose the association of pre- and post-stroke glycemic status with clinical outcome in patients with spontaneous intracerebral hemorrhage (sICH). It was a multicenter, prospective, observational cohort study, conducted in 13 hospitals in Beijing from January 2014 to September 2016. The association of admission random blood glucose (RBG), fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) with clinical outcome at 90 days after sICH onset were analyzed comprehensively. Poor outcome was defined as death or modified Rankin Scale (mRS) score >2. The results showed that elevated RBG and FBG were associated with larger hematoma volume, lower GCS, higher NIHSS (P < 0.001), and poor outcome, but HbA1c was not (P > 0.05). In stratified analysis, the association of poor outcome with elevated FBG or RBG retained statistical significance just in patients without diabetes. Kaplan-Meier curve and Cox regression showed that patients with elevated FBG or RBG had significantly higher risk of death within 90 days (P < 0.05). So we conclude that poststroke hyperglycemia was associated with larger hematoma volume, severe neurological damage and poor clinical outcome, but HbA1c was not relevant to hematoma volume or clinical outcome in patients with sICH.

Chungkookjang, a soy food, fermented with Bacillus amyloliquefaciens protects gerbils against ishcmeic stroke injury, and post-stroke hyperglycemia.

Chungkookjang is a traditional Korean fermented soybean food with anti-diabetic and thrombolytic activity. It may also have anti-stroke activity. We determined that chungkookjang made with Sunchang Research Center for Fermentation Microbes 100730 and 100731 strains of Bacillus amyloliquefaciens(SRCM100730; CKJ730) and SRCM100731(CKJ731) protected against ischemic stroke and post-stroke hyperglycemia in Mongolian gerbils with ischemic stroke induced by transient occlusion of the carotid arteries. Gerbil fed 4.5% cooked soybeans (CSB), CKJ730, CKJ731, or cellulose (negative-control) in 40 energy% fat diets for 3 weeks, and then had artery occlusion for 8 min and continued taking the assigned diet for 5 weeks. CKJ730 and CKJ731 had thrombolytic activity and prevented neuronal cell death. Consequently, they improved short-term memory and spontaneous alteration compared to the negative-control. CKJ730 and CKJ731 improved neurological symptoms including drooped eyes, crouched posture, flexor reflex, and walking patterns the most among the stroke-induced gerbils. CKJ730 and CKJ731 increased active time, grip strength, and blood flow measured by Doppler compared to the negative-control. CKJ730 protected against post-stroke glucose dysregulation by restoring β-cell mass in the gerbils with transient artery occlusion. Serum tumor necrosis factor-α and interleukin-1β levels were lower in CKJ730 and CKJ731 than the negative-control. CSB also improved glucose metabolism and suppressed inflammatory cytokines, but less than CKJ730 and CKJ731. Clostridia increased, and Bacteriodia slightly decreased in the negative-control group, compared to the normal-control. CKJ730 and CKJ731 changed the amounts of Bacteriodia and Clostridia to be similar to normal-control. In conclusion, the daily intake of chungkookjang fermented with B. amyloliquefaciens improved the gut microbiome, increased blood flow to the brain, suppressed systemic inflammation, and may reduce the susceptibility to injury from ischemic stroke in gerbils subjected to ischemic injury.

Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia.

Rationale Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke. Design TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Conclusion TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia. Trial registration: ClinicalTrials.gov/ANZCTR NTA1127.

Autophagy- and MMP-2/9-mediated Reduction and Redistribution of ZO-1 Contribute to Hyperglycemia-increased Blood–Brain Barrier Permeability During Early Reperfusion in Stroke

Post-stroke hyperglycemia during early reperfusion increases blood–brain barrier (BBB) permeability and subsequently aggravates brain injury and clinical prognosis. The decreased level of tight junction proteins (TJPs) has been reported but the underlying mechanism remains largely elusive. Herein we designed to investigate the detailed molecular events in brain microvascular endothelial cells (BMECs) ex and in vivo. After oxygen–glucose deprivation (OGD) for 90 min and reperfusion with 8 or 16 mM glucose for 30 min, glucose at 16 mM caused significant decrease in the TJP expression and particularly ZO-1 redistribution from membrane to cytoplasm of BMECs. High glucose also markedly promoted the secretion of MMP-2/9 and oxidative/nitrosative stress, enhanced autophagy and increased the Caveolin-1 and LAMP-2 expression. Moreover, in vivo experiments demonstrated that rapamycin-enhanced autophagy further caused ZO-1 reduction and the increased BBB permeability. Therefore, high-glucose exposure in the early reperfusion causes the BBB disruption, with MMP-2/9-mediated extracellular degradation, caveolin-1-mediated intracellular translocation and autophagy-lysosome-mediated degradation of ZO-1 protein all together involved in the process. The role of MMP-2/-9 and autophagy in the modulation of paracellular permeability was confirmed by pharmacological inhibition. Therefore, our findings may provide new insights into targeting ZO-1 regulation for the purpose of significantly improving the clinical prognosis of ischemic stroke.

Abstract WP191: DM is Not Related With Poor Outcome in Acute Ischemic Stroke. the GLIAS-II Study

Backgrounds: Diabetes Mellitus (DM) has been widely associated with poor outcome after an ischemic stroke (IS). However the underlying mechanisms are not well elucidated. We aim to study whether the outcome in stroke patients with DM is independent of comorbidity, the development of poststroke hyperglycaemia or due to higher glycaemic variability. Methods: Secondary analysis of the GLIAS-II study (multicenter, prospective, observational academic cohort study). We compared outcomes (in-hospital complications; mortality; death or dependence (mRS &gt;2); and stroke recurrence at 3 months) in two study groups: patients with prior diagnosis of DM (DM group) vs. patients without DM (non DM group). We performed multivariate analysis in order to adjust the effect of DM on stroke outcomes by comorbidity (Charlson index), poststroke hyperglycaemia (&gt;155 mg/dL) during the fist 48 h and glycaemic variability (standard deviation and coefficient of variation). Results: We included 213 patients, 64 (30%) with DM. The baseline characteristics (age, sex, stroke severity and the proportion of patients treated with intravenous thrombolysis) were similar between groups. There were no differences in in-hospital complications: pneumonia (4.7% vs. 3.4%; P=.699); urine infection (4.7% vs.1.3%; P =.161); cerebral edema (6.2% vs. 4%; P=.492); or symptomatic hemorrhagic transformation of the stroke (1.6 vs. 0.7%; P =.512) between DM and non DM groups. There was no difference between groups in mortality (12.7 vs. 5.7%; P=.096); death or dependency at 3 months (31.7% vs. 26.4%; P =.500), neither in stroke recurrence (3.1 vs. 4%; P =1.000) at 3 months. After adjusting for other prognostic factors, DM was not associated with any of the studied outcomes, whilst glycaemic variability was independently associated with mortality (p=0.032) and hyperglycemia within 48 hours with death or dependence (p=0.049). Conclusion: DM itself was not associated with poor outcome in acute stroke patients admitted to SU, being glycaemic variability and poststroke hyperglycemia risk factors for mortality and death or dependence respectively.

Diabetes and the central nervous system

Diabetes increases the risk of stroke by afactor of 2-4. For primary and secondary stroke prevention, strict glycemic control alone was not superior to standard treatment. However, the risk of stroke in patients with diabetes could be reduced by multimodal risk interventions during the last 20years by about 50%. Increased glucose levels (poststroke hyperglycemia (PSH)) which indicate aworse prognosis develop in 50% of stroke patients. The potentially beneficial effect of strict glycemic control in PSH by i. v. insulin was neutralized by negative effects of an increased rate of hypoglycemic episodes. Diabetes leads to an increased risk of vascular dementia, but also of the neurodegenerative Alzheimer 's type. Recurrent hypoglycemic episodes affect the timely perception of hypoglycemia by cerebral-mediated mechanisms, which reduces the possibility of counterreactions.