|Year : 2022 | Volume
| Issue : 4 | Page : 83-88
Mini review: Hyperglycemia in ischemic stroke
Honglian Duan1, Wesley Kohls2, Roxanne Ilagan2, Xiaokun Geng3, Yuchuan Ding2
1 Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
2 Department of Neurosurgery, Wayne State University School of Medicine, Michigan, United States
3 Department of Neurology, Beijing Luhe Hospital, Capital Medical University; Department of Neurology, Luhe Institute of Neuroscience, Capital Medical University, Beijing, China
|Date of Submission||16-Nov-2022|
|Date of Decision||03-Dec-2022|
|Date of Acceptance||07-Dec-2022|
|Date of Web Publication||27-Dec-2022|
Department of Neurology, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou, Beijing 101149
Source of Support: None, Conflict of Interest: None
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.
Keywords: Acute ischemic stroke, gluconeogenesis, glucose metabolism, hyperglycemia, insulin resistance, liver
|How to cite this article:|
Duan H, Kohls W, Ilagan R, Geng X, Ding Y. Mini review: Hyperglycemia in ischemic stroke. Environ Dis 2022;7:83-8
| Introduction|| |
Stroke, the second leading cause of death worldwide, continues to grow, affecting approximately 12.2 million people, with 6.5 million deaths, in 2019. Strokes result in persistent neurological deficits due to cerebral ischemia and metabolic abnormalities. Any improvement in functional outcomes is necessary for lessening the worldwide health burden of stroke., Even without a history of diabetes mellitus, reports demonstrate that approximately one-third of patients develop hyperglycemia after an acute ischemic stroke (AIS).,,, This review will discuss the relationship between AIS, hyperglycemia, and the inflammatory pathway that contributes to hepatic gluconeogenesis and insulin resistance. Doing so, we will attempt to identify a more selective approach to evaluate poststroke hyperglycemia as well as treatment regimens that address the underlying mechanisms that cause an acute elevation of blood glucose.
| Hyperglycemia After Acute Ischemic Stroke|| |
The large incidence of hyperglycemia after AIS is due to substantial brain damage activating the acute stress response, involving the hypothalamic–pituitary–adrenal axis and sympathetic nervous system. Metabolic abnormalities, such as hyperglycemia, are likely to develop in patients following AIS, which may worsen their clinical outcomes. Hyperglycemia on admission was an independent marker of reduced cognitive and functional outcomes, larger ischemia, and increased mortality risk. Furthermore, worse functional outcomes were directly related to higher blood glucose levels at admission in patients after intravenous thrombolysis (IVT) and mechanical thrombectomy, likely due to early reperfusion injury and increased hemorrhagic transformation., In addition, studies showed that patients exposed to stress-related hyperglycemia without a diagnosis of diabetes mellitus (DM) were more susceptible to morbidity and mortality than those with a diagnosis of DM.,, The differences in morbidity and mortality may be attributed to adaptions in diabetic patients to chronic hyperglycemia, as these patients were more tolerant to varying blood glucose levels.
In contrast, several reports did not demonstrate an association between poststroke hyperglycemia and poor prognosis., A potential reason behind these inconsistent results may be due to differing definitions of hyperglycemia after AIS. Fasting glucose, collected within 24 h of symptom onset, or random glucose on admission was gathered in some studies to account for blood glucose changes due to the stress response to cerebral ischemia. Absolute glucose levels affected by food intake and previous blood glucose status provide minimal prognostic insight because there is no consideration for the natural interpatient variation of background plasma glucose levels.
The acute elevation of plasma glucose levels instead of hyperglycemia itself has been proposed to play a more prominent role in precipitating poor clinical outcomes. Stress hyperglycemia, defined as the ratio of plasma glucose-to-glycated hemoglobin ratio (GAR), helps determine the extent of acute plasma glucose elevation compared to absolute glucose levels. Recent studies on stroke have used GAR as an index of the changes in glucose caused by stress after AIS. GAR was associated with a greater risk of adverse outcomes, which included poststroke dysfunction, infectious complications, and all-cause death. The index was also associated with hemorrhagic transformation in AIS patients. Specifically, there was a direct relationship between GAR and increased risk of stroke-associated pneumonia in patients without diabetes. As for patients who received IVT, a higher GAR predicted a greater risk of early neurological degeneration and worse functional outcome at discharge for patients with severe stress hyperglycemia.,, For patients who received mechanical thrombectomy, GAR was a significant predictor of poor 3-month outcomes, 3-month mortality, and symptomatic intracranial hemorrhage.,
| Current Treatments For Stress-Induced Hyperglycemia|| |
The negative effects of stress-induced hyperglycemia suggest an urgent need for lowering blood glucose levels after ischemic strokes. However, the results of open cohort and randomized studies did not confirm the benefit of intensive insulin treatment in blood glucose control. Intense postischemic insulin infusion for 24 h in AIS patients did not demonstrate benefits in the randomized UK Glucose Insulin in Stroke Trial. Reviews,, and a recent study also found no significant difference in favorable outcomes after intensive insulin treatment to keep serum glucose between 4 and 7.5 mmol/L. Therefore, the guidelines for the European Stroke Organization, American Heart Association, and American Stroke Association recommend blood glucose control after AIS in the range of 140–180 mg/dl (7.7–10 mmol/L).,
In addition to regulating blood sugar, glycemic control medications may also have neuroprotective effects. Acarbose guards against lysosomal and mitochondrial malfunction. Inhibition of the P53 protein, which functions as a signaling point for the convergence of necrosis and apoptosis in cerebral ischemia, alters gene expression associated with inflammation, cell survival, and regeneration., Metformin has been found to enhance oxidative stress levels and neurological functioning in acute stroke patients with DM II. Two of the newer classes of glucose-lowering drugs, glucagon-like peptide-1 receptor agonists (GLP-1Ras) and dipeptidyl peptidase-IV inhibitors, are primarily used in the treatment of DM. Several studies emphasized the neuroprotective properties of GLP-1 Ras (e.g., liraglutide and exenatide), through anti-edema and anti-apoptotic effects, and support of the blood–brain barrier integrity and microcirculation., The beneficial role of GLP-1Ras in the treatment of hyperglycemia in AIS patients was confirmed by clinical trials.,
| Liver and Hyperglycemia|| |
Under normal physiological conditions, the liver plays a major role in glucose homeostasis through interactions with various glucose metabolism pathways including gluconeogenesis, glycogenesis, glycolysis, and glycogenolysis. The stability of blood glucose is under the joint action of several key enzymes of glucose metabolism, insulin, glucagon, and epinephrine, as well as numerous cytokines and transcription factors. The vast majority of gluconeogenesis and glycogenolysis occurs in the liver. This is due to the primarily hepatic expression of the enzyme, glucose-6-phosphatase (G6Pase), as opposed to the minor amount of G6Pase expression in the kidney and intestines.,,,,, Reports demonstrated that the mechanism of hyperglycemia after stroke [Figure 1] is due to increased hepatic gluconeogenesis and reduced insulin sensitivity. In animal models with focal brain ischemia, upregulation of liver gluconeogenesis was regarded as an important mechanism in the development of hyperglycemia., The development of poststroke hyperglycemia coincided with decreased skeletal muscle insulin signaling, increased hepatic gluconeogenesis, and the secretion of counter-regulatory hormones (e.g., glucagon, norepinephrine, and corticosterone). Glucagon, epinephrine, and glucocorticoids promote gluconeogenesis through the increased expression of phosphoenolpyruvate carboxykinase (PEPCK), an important hepatic gluconeogenesis enzyme. One study showed that these hormones enhanced glucose levels through their augmentation of p53. This was due to their inability to increase glucose levels after administration of these hormones to liver-specific p53-deficient mice and p53-deficient human hepatocytes. Acute cerebral ischemia can activate inflammatory pathways in the liver by increasing the levels of catecholamines. This is due to increased expression of hepatic tumor necrosis factor (TNF)-α, increased activity of intracellular inhibitor κB kinase β (IKK-β), nuclear factor-κB, and Jun N-terminal kinase 1/2, and increased endoplasmic reticulum stress, which all contribute to poststroke hepatic insulin resistance. In rats, β-adrenergic antagonist (propranolol) administration, before the development of cerebral ischemia, partially repaired hepatic insulin signaling pathways and reduced the poststroke hepatic inflammatory pathway. Interleukin-13 (IL-13), a member of the T helper cell 2 cytokine family, was reported to be involved in both glucose metabolism and the regulation of the immune response. Hyperglycemia occurred after genetic ablation of IL-13 in mice, which eventually progressed to metabolic dysfunction and hepatic insulin resistance. The upregulation of hepatic gluconeogenesis enzymes in these IL-13-deficient mice contributed to the dysregulation of glucose metabolism, as gluconeogenic gene transcription is inhibited by IL-13 through direct action on hepatocytes by the signal transducers and activator of transcription-3 (STAT3), a noncanonical downstream effector. The pro-inflammatory states were counteracted by IL-13 treatment through the enhancement of STAT6 and STAT3 effectors that mediate immune and metabolic pathways, respectively. The effects on these pathways resolved the poststroke hyperglycemia pathological changes and reduced the size of infarctions in middle cerebral artery occlusion (MCAO) rats. In addition, the gluconeogenesis rate-limiting enzymes, pyruvate carboxylase, PEPCK, and G6Pase were elevated after brain ischemia. On the 1st day following MCAO of the rat specimens, gluconeogenic enzyme levels were elevated whereas insulin receptor expression levels in the liver and skeletal muscle were decreased. The crucial transcription factor forkhead box protein O1 (FoxO1), which regulates hepatic gluconeogenesis, is involved in the cortisol pathway, as glucocorticoid receptor activation increases transcription and subsequent expression of hepatic FoxO1. There is also an upregulation of other transcription co-activators (e.g., cAMP-responsive element-binding protein), along with hepatic FoxO1, to amplify and promote the expression of gluconeogenesis enzymes in the liver. Studies demonstrated that glucose levels rose after 12 h, peaked after 24 h, and practically normalized on the 3rd day. In rats with global cerebral ischemia, there was decreased hepatic expression of mRNA for pyruvate carboxylase (50%), PEPCK (56%), and G6Pase (80%) 24 h after ischemia, suggesting that metabolism quickly responded to the new, poststroke, conditions.
|Figure 1: The mechanism of hyperglycemia after stroke. Increased hepatic gluconeogenesis and decreased insulin sensitivity are the causes of poststroke hyperglycemia. The application of β-adrenergic antagonist can reduce insulin resistance. By enhancing the effect of STAT3: signal transducers and activator of transcription-3, IL-13 inhibits the gene transcription for gluconeogenesis and downregulates gluconeogenesis. See the main text for more specific regulatory pathways. IL-13: Interleukin-13|
Click here to view
Insulin primarily regulates blood glucose homeostasis through increased uptake of glucose in peripheral tissue (e.g., skeletal muscle) and inhibition of hepatic gluconeogenesis. Insulin regulates hepatic gluconeogenesis through insulin receptor binding, which activates the insulin receptor substrate/phosphatidylinositol 3-kinase/AKT pathway., Pro-inflammatory cytokines, such as TNF-α, reduce insulin receptor expression, and subsequently reduce insulin sensitivity in the liver. Cerebral ischemia has been shown to cause adrenergic stimulation and the release of circulating catecholamines, which upregulates hepatic expression of pro-inflammatory cytokines, ultimately resulting in hepatic insulin resistance., Clinical studies showed that insulin resistance is associated with poor outcomes after AIS. A study of patients undertaking IVT demonstrated that insulin resistance, assessed by the homeostasis model assessment-insulin resistance (HOMA-IR), was associated with poor outcomes in AIS patients. Another study indicated that insulin resistance occurred in AIS patients with normal range plasma glucose levels, and these patients had an association with the poor functional outcome of nondiabetic stroke. In nondiabetic mellitus patients with the highest quartile of log HOMA-IR index scores, there was an independent association with poor prognosis after adjustments for age and sex in a univariable analysis. This finding indicates that insulin resistance occurs in postischemic stroke patients with normal blood glucose and that treatment with a β-adrenergic antagonist (propranolol), which can partially reduce the poststroke hepatic inflammatory pathway to repair hepatic insulin signaling pathways, should be considered in patients with a normal blood glucose.
| Conclusion|| |
Given the growing incidence of stroke and its associated complications, understanding the role of stress-related hyperglycemia is imperative in refining and improving the treatment of cerebral ischemia. Addressing the underlying hepatic inflammatory mechanism of poststroke hyperglycemia should be the focus of poststroke hyperglycemia treatment. The index of stress-induced hyperglycemia, GAR, quantifies the acute elevation of glucose and should be used to identify patients who might benefit from targeted antihyperglycemic therapy. Afterward, studies should be conducted to re-evaluate the success of antihyperglycemic agents in treating the manifestation of the hepatic inflammatory process, an acute elevation of blood glucose, thereby properly identifying the impact of antihyperglycemic agents on poststroke outcomes.
We conclude that a targeted approach to acute elevations of blood glucose in the setting of AIS could pave the way for improved outcomes with antihyperglycemic therapy. This approach can alleviate the effects of the hepatic inflammatory pathway that result in increased hepatic gluconeogenesis and reduced insulin sensitivity.
Financial support and sponsorship
This work was partially supported by the National Natural Science Foundation of China (82002382, 81871838, and 8200090876), the Youth Plan of Beijing Luhe Hospital (LHYY2021-LC08), the Science Foundation of Capital Medical University (PYZ21170), the Yunhe talent Program of Beijing Tongzhou District, and the Laboratory Development Funds of Beijing Luhe Hospital (2022).
Conflicts of interest
Dr. Yuchuan Ding is an Editor-in-Chief, Dr. Xiaokun Geng is an Editorial Board member of Environmental Disease. The article was subject to the journal's standard procedures, with peer review handled independently of them and their research groups..
| References|| |
GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the global burden of disease study 2019. Lancet Neurol 2021;20:795-820.
Hollist M, Morgan L, Cabatbat R, Au K, Kirmani MF, Kirmani BF. Acute stroke management: Overview and recent updates. Aging Dis 2021;12:1000-9.
Wills M, Ding Y. Beyond reperfusion: Enhancing endogenous restorative functions after an ischemic stroke. Brain Circ 2020;6:223-4. [Full text]
Li WA, Moore-Langston S, Chakraborty T, Rafols JA, Conti AC, Ding Y. Hyperglycemia in stroke and possible treatments. Neurol Res 2013;35:479-91.
Yao M, Ni J, Zhou L, Peng B, Zhu Y, Cui L, et al
. Elevated fasting blood glucose is predictive of poor outcome in non-diabetic stroke patients: A sub-group analysis of SMART. PLoS One 2016;11:e0160674.
Jiang Y, Liu N, Han J, Li Y, Spencer P, Vodovoz SJ, et al
. Diabetes mellitus/poststroke hyperglycemia: A detrimental factor for tPA thrombolytic stroke therapy. Transl Stroke Res 2021;12:416-27.
Almobarak AO, Badi S, Elmadhoun WM, Tahir H, Ahmed MH. The prevalence and risk factors of stroke among Sudanese individuals with diabetes: Cross-sectional survey. Brain Circ 2020;6:26-30. [Full text]
Christensen H, Boysen G, Johannesen HH. Serum-cortisol reflects severity and mortality in acute stroke. J Neurol Sci 2004;217:175-80.
Robbins NM, Swanson RA. Opposing effects of glucose on stroke and reperfusion injury: Acidosis, oxidative stress, and energy metabolism. Stroke 2014;45:1881-6.
Tsivgoulis G, Katsanos AH, Mavridis D, Lambadiari V, Roffe C, Macleod MJ, et al
. Association of baseline hyperglycemia with outcomes of patients with and without diabetes with acute ischemic stroke treated with intravenous thrombolysis: A propensity score-matched analysis from the SITS-ISTR registry. Diabetes 2019;68:1861-9.
Suissa L, Panicucci E, Perot C, Romero G, Gazzola S, Laksiri N, et al
. Effect of hyperglycemia on stroke outcome is not homogeneous to all patients treated with mechanical thrombectomy. Clin Neurol Neurosurg 2020;194:105750.
Rosso C, Baronnet F, Diaz B, Le Bouc R, Frasca Polara G, Moulton EJ, et al
. The silver effect of admission glucose level on excellent outcome in thrombolysed stroke patients. J Neurol 2018;265:1684-9.
Krinsley JS, Meyfroidt G, van den Berghe G, Egi M, Bellomo R. The impact of premorbid diabetic status on the relationship between the three domains of glycemic control and mortality in critically ill patients. Curr Opin Clin Nutr Metab Care 2012;15:151-60.
Zhu B, Pan Y, Jing J, Meng X, Zhao X, Liu L, et al
. Stress hyperglycemia and outcome of non-diabetic patients after acute ischemic stroke. Front Neurol 2019;10:1003.
Merlino G, Pez S, Tereshko Y, Gigli GL, Lorenzut S, Surcinelli A, et al
. Stress hyperglycemia does not affect clinical outcome of diabetic patients receiving intravenous thrombolysis for acute ischemic stroke. Front Neurol 2022;13:903987.
Ferrari F, Moretti A, Villa RF. Hyperglycemia in acute ischemic stroke: Physiopathological and therapeutic complexity. Neural Regen Res 2022;17:292-9.
] [Full text]
Ntaios G, Abatzi C, Alexandrou M, Lambrou D, Chatzopoulos S, Egli M, et al. Persistent hyperglycemia at 24-48 h in acute hyperglycemic stroke patients is not associated with a worse functional outcome. Cerebrovasc Dis 2011;32:561-6.
Ntaios G, Egli M, Faouzi M, Michel P. J-shaped association between serum glucose and functional outcome in acute ischemic stroke. Stroke 2010;41:2366-70.
Roberts G, Sires J, Chen A, Thynne T, Sullivan C, Quinn S, et al.
A comparison of the stress hyperglycemia ratio, glycemic gap, and glucose to assess the impact of stress-induced hyperglycemia on ischemic stroke outcome. J Diabetes 2021;13:1034-42.
Guo YW, Wu TE, Chen HS. Prognostic factors of mortality among patients with severe hyperglycemia. Am J Manage Care 2015;21:e9-22.
Su YW, Hsu CY, Guo YW, Chen HS. Usefulness of the plasma glucose concentration-to-HbA (1c) ratio in predicting clinical outcomes during acute illness with extreme hyperglycaemia. Diabetes Metab 2017;43:40-7.
Cai ZM, Zhang MM, Feng RQ, Zhou XD, Chen HM, Liu ZP, et al
. Fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality among Chinese in-hospital patients with acute stroke: A 12-month follow-up study. BMC Geriatr 2022;22:508.
Yuan C, Chen S, Ruan Y, Liu Y, Cheng H, Zeng Y, et al
. The stress hyperglycemia ratio is associated with hemorrhagic transformation in patients with acute ischemic stroke. Clin Interv Aging 2021;16:431-42.
Wang L, Cheng Q, Hu T, Wang N, Wei X, Wu T, et al
. Impact of stress hyperglycemia on early neurological deterioration in acute ischemic stroke patients treated with intravenous thrombolysis. Front Neurol 2022;13:870872.
Ngiam JN, Cheong CW, Leow AS, Wei YT, Thet JK, Lee IY, et al
. Stress hyperglycaemia is associated with poor functional outcomes in patients with acute ischaemic stroke after intravenous thrombolysis. QJM 2022;115:7-11.
Merlino G, Smeralda C, Gigli GL, Lorenzut S, Pez S, Surcinelli A, et al
. Stress hyperglycemia is predictive of worse outcome in patients with acute ischemic stroke undergoing intravenous thrombolysis. J Thromb Thrombolysis 2021;51:789-97.
Cannarsa GJ, Wessell AP, Chryssikos T, Stokum JA, Kim K, De Paula Carvalho H, et al
. Initial stress hyperglycemia is associated with malignant cerebral edema, hemorrhage, and poor functional outcome after mechanical Thrombectomy. Neurosurgery 2022;90:66-71.
Merlino G, Pez S, Gigli GL, Sponza M, Lorenzut S, Surcinelli A, et al
. Stress hyperglycemia in patients with acute ischemic stroke due to large vessel occlusion undergoing mechanical thrombectomy. Front Neurol 2021;12:725002.
Gray CS, Hildreth AJ, Sandercock PA, O'Connell JE, Johnston DE, Cartlidge NE, et al
. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: The UK glucose insulin in stroke trial (GIST-UK). Lancet Neurol 2007;6:397-406.
Bellolio MF, Gilmore RM, Ganti L. Insulin for glycaemic control in acute ischaemic stroke. Cochrane Database Syst Rev 2014;(1):CD005346.
Ntaios G, Papavasileiou V, Bargiota A, Makaritsis K, Michel P. Intravenous insulin treatment in acute stroke: A systematic review and meta-analysis of randomized controlled trials. Int J Stroke 2014;9:489-93.
Yamada T, Shojima N, Noma H, Yamauchi T, Kadowaki T. Glycemic control, mortality, and hypoglycemia in critically ill patients: A systematic review and network meta-analysis of randomized controlled trials. Intensive Care Med 2017;43:1-15.
Johnston KC, Bruno A, Pauls Q, Hall CE, Barrett KM, Barsan W, et al.
Intensive versus standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: The SHINE randomized clinical trial. JAMA 2019;322:326-35.
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al
. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic Stroke: A guideline for healthcare professionals from the American heart association/American stroke association. Stroke 2019;50:e344-418.
Fuentes B, Ntaios G, Putaala J, Thomas B, Turc G, Díez-Tejedor E, et al
. European stroke organization (ESO) guidelines on glycaemia management in acute stroke. Eur Stroke J 2018;3:5-21.
Das J, Mahammad FS, Krishnamurthy RG. An integrated chemo-informatics and in vitro
experimental approach repurposes acarbose as a post-ischemic neuro-protectant. 3 Biotech 2022;12:71.
Tseng CH. Dementia risk in type 2 diabetes patients: Acarbose use and its joint effects with metformin and pioglitazone. Aging Dis 2020;11:658-67.
Zhao M, Li XW, Chen Z, Hao F, Tao SX, Yu HY, et al
. Neuro-protective role of metformin in patients with acute stroke and type 2 diabetes mellitus via AMPK/mammalian target of rapamycin (mTOR) signaling pathway and oxidative stress. Med Sci Monit 2019;25:2186-94.
Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, et al.
The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK pathways. Sci Rep 2016;6:26859.
Shan Y, Tan S, Lin Y, Liao S, Zhang B, Chen X, et al
. The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke. J Neuroinflammation 2019;16:242.
Barkas F, Elisaf M, Milionis H. Protection against stroke with glucagon-like peptide 1 receptor agonists: A systematic review and meta-analysis. Eur J Neurol 2019;26:559-65.
Daly SC, Chemmanam T, Loh PS, Gilligan A, Dear AE, Simpson RW, et al
. Exenatide in acute ischemic stroke. Int J Stroke 2013;8:E44.
Rajas F, Bruni N, Montano S, Zitoun C, Mithieux G. The glucose-6 phosphatase gene is expressed in human and rat small intestine: Regulation of expression in fasted and diabetic rats. Gastroenterology 1999;117:132-9.
van Schaftingen E, Gerin I. The glucose-6-phosphatase system. Biochem J 2002;362:513-32.
Varga V, Murányi Z, Kurucz A, Marcolongo P, Benedetti A, Bánhegyi G, et al. Species-Specific Glucose-6-Phosphatase Activity in the Small Intestine-Studies in Three Different Mammalian Models. Int J Mol Sci 2019;20:5039.
Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, Pazos-García C. Liver glucose metabolism in humans. Biosci Rep 2016;36(6):e00416.
Ren C, Liu Y, Stone C, Li N, Li S, Li H, et al
. Limb remote ischemic conditioning ameliorates cognitive impairment in rats with chronic cerebral hypoperfusion by regulating glucose transport. Aging Dis 2021;12:1197-210.
Chaturvedi P, Singh AK, Tiwari V, Thacker AK. Brain-derived neurotrophic factor levels in acute stroke and its clinical implications. Brain Circ 2020;6:185-90. [Full text]
Liao KY, Chen CJ, Hsieh SK, Pan PH, Chen WY. Interleukin-13 ameliorates postischemic hepatic gluconeogenesis and hyperglycemia in rat model of stroke. Metab Brain Dis 2020;35:1201-10.
Harada S, Fujita-Hamabe W, Tokuyama S. Ischemic stroke and glucose intolerance: A review of the evidence and exploration of novel therapeutic targets. J Pharmacol Sci 2012;118:1-13.
Wang YY, Lin SY, Chuang YH, Sheu WH, Tung KC, Chen CJ. Activation of hepatic inflammatory pathways by catecholamines is associated with hepatic insulin resistance in male ischemic stroke rats. Endocrinology 2014;155:1235-46.
Chen WY, Mao FC, Liu CH, Kuan YH, Lai NW, Wu CC, et al
. Chromium supplementation improved post-stroke brain infarction and hyperglycemia. Metab Brain Dis 2016;31:289-97.
Gonzalez-Rellan MJ, Fondevila MF, Fernandez U, Rodríguez A, Varela-Rey M, Veyrat-Durebex C, et al
. O-GlcNAcylated p53 in the liver modulates hepatic glucose production. Nat Commun 2021;12:5068.
Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR, et al
. Direct control of hepatic glucose production by interleukin-13 in mice. J Clin Invest 2013;123:261-71.
Harada S, Fujita-Hamabe W, Tokuyama S. Effect of orexin a on post-ischemic glucose intolerance and neuronal damage. J Pharmacol Sci 2011;115:155-63.
Guo S, Mangal R, Dandu C, Geng X, Ding Y. Role of forkhead box protein O1 (FoxO1) in stroke: A literature review. Aging Dis 2022;13:521-33.
Harada S, Fujita WH, Shichi K, Tokuyama S. The development of glucose intolerance after focal cerebral ischemia participates in subsequent neuronal damage. Brain Res 2009;1279:174-81.
Sá-Nakanishi AB, de Oliveira MC, O Pateis V, P Silva LA, Pereira-Maróstica HV, Gonçalves GA, et al
. Glycemic homeostasis and hepatic metabolism are modified in rats with global cerebral ischemia. Biochim Biophys Acta Mol Basis Dis 2020;1866:165934.
Carrera Boada CA, Martínez-Moreno JM. Pathophysiology of diabetes mellitus type 2: Beyond the duo "insulin resistance-secretion deficit". Nutr Hosp 2013;28 Suppl 2:78-87.
Klover PJ, Mooney RA. Hepatocytes: Critical for glucose homeostasis. Int J Biochem Cell Biol 2004;36:753-8.
Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: A metabolic pathway to chronic liver disease. Hepatology 2005;42:987-1000.
Wong CH, Jenne CN, Lee WY, Léger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 2011;334:101-5.
Wu J, Wu Z, He A, Zhang T, Zhang P, Jin J, et al
. Genome-wide screen and validation of microglia pro-inflammatory mediators in stroke. Aging Dis 2021;12:786-800.
Bas DF, Ozdemir AO, Colak E, Kebapci N. Higher insulin resistance level is associated with worse clinical response in acute ischemic stroke patients treated with intravenous thrombolysis. Transl Stroke Res 2016;7:167-71.
Chang Y, Kim CK, Kim MK, Seo WK, Oh K. Insulin resistance is associated with poor functional outcome after acute ischemic stroke in non-diabetic patients. Sci Rep 2021;11:1229.