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 Table of Contents  
Year : 2022  |  Volume : 7  |  Issue : 4  |  Page : 83-88

Mini review: Hyperglycemia in ischemic stroke

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 Submission16-Nov-2022
Date of Decision03-Dec-2022
Date of Acceptance07-Dec-2022
Date of Web Publication27-Dec-2022

Correspondence Address:
Xiaokun Geng
Department of Neurology, Beijing Luhe Hospital, Capital Medical University, No. 82 Xinhua South Road, Tongzhou, Beijing 101149
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ed.ed_26_22

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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

How to cite this URL:
Duan H, Kohls W, Ilagan R, Geng X, Ding Y. Mini review: Hyperglycemia in ischemic stroke. Environ Dis [serial online] 2022 [cited 2023 Mar 26];7:83-8. Available from: http://www.environmentmed.org/text.asp?2022/7/4/83/365627

  Introduction Top

Stroke, the second leading cause of death worldwide, continues to grow, affecting approximately 12.2 million people, with 6.5 million deaths, in 2019.[1] 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.[2],[3] Even without a history of diabetes mellitus, reports demonstrate that approximately one-third of patients develop hyperglycemia after an acute ischemic stroke (AIS).[4],[5],[6],[7] 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 Top

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.[8] Metabolic abnormalities, such as hyperglycemia, are likely to develop in patients following AIS, which may worsen their clinical outcomes.[9] Hyperglycemia on admission was an independent marker of reduced cognitive and functional outcomes, larger ischemia, and increased mortality risk.[10] 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.[11],[12] 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.[13],[14],[15] 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.[16]

In contrast, several reports did not demonstrate an association between poststroke hyperglycemia and poor prognosis.[17],[18] 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.[19]

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.[20] 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.[21] 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.[22] The index was also associated with hemorrhagic transformation in AIS patients.[23] 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.[24],[25],[26] For patients who received mechanical thrombectomy, GAR was a significant predictor of poor 3-month outcomes, 3-month mortality, and symptomatic intracranial hemorrhage.[27],[28]

  Current Treatments For Stress-Induced Hyperglycemia Top

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.[29] Reviews[30],[31],[32] and a recent study[33] 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).[34],[35]

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.[36],[37] Metformin has been found to enhance oxidative stress levels and neurological functioning in acute stroke patients with DM II.[38] 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.[39],[40] The beneficial role of GLP-1Ras in the treatment of hyperglycemia in AIS patients was confirmed by clinical trials.[41],[42]

  Liver and Hyperglycemia Top

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.[43],[44],[45],[46],[47],[48] Reports demonstrated that the mechanism of hyperglycemia after stroke [Figure 1] is due to increased hepatic gluconeogenesis and reduced insulin sensitivity.[49] In animal models with focal brain ischemia, upregulation of liver gluconeogenesis was regarded as an important mechanism in the development of hyperglycemia.[50],[51] 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).[52] 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.[53] 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.[51] 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.[54] 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.[49] 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.[55] 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.[56] Studies demonstrated that glucose levels rose after 12 h, peaked after 24 h, and practically normalized on the 3rd day.[57] 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.[58]
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

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Insulin primarily regulates blood glucose homeostasis through increased uptake of glucose in peripheral tissue (e.g., skeletal muscle) and inhibition of hepatic gluconeogenesis.[59] Insulin regulates hepatic gluconeogenesis through insulin receptor binding, which activates the insulin receptor substrate/phosphatidylinositol 3-kinase/AKT pathway.[60],[61] 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.[62],[63] 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.[64] 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.[65] 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 Top

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..

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