Ischemic Stroke and Glucose Intolerance: a Review of the Evidence and Exploration of Novel Therapeutic Targets

Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

doi:10.1254/jphs.11r04cr

Cited by 43 publications

(29 citation statements)

References 103 publications

(97 reference statements)

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“…In contrast, the administration of intravenous insulin with the objective of maintaining serum glucose within a specific range in the first hours of acute ischemic stroke 1) does not provide benefit in terms of functional outcome, death, or improvement in final neurologic deficit and 2) significantly increased the number of hypoglycemic episodes (Bellolio et al, 2011), suggesting the need for ongoing discussion about the importance of postischemic glucose metabolism regulation. We recently reported that focal cerebral ischemia per se causes a hyperglycemic condition (i.e., postischemic glucose intolerance) and that this may worsen the ischemic neuronal damage in mice (Harada et al, 2009a(Harada et al, , 2012b.…”

Section: Introductionmentioning

confidence: 99%

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Harada

Yamazaki

Tokuyama

2012

J Pharmacol Exp Ther

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Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N9-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A.

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Section: Introductionmentioning

confidence: 99%

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Harada

Yamazaki

Tokuyama

2012

J Pharmacol Exp Ther

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“…This release results in insulin resistance, glycogenolysis, gluconeogenesis, proteolysis and lipolysis [29,30]. Furthermore, there is substantial evidence that stroke can induce hyperglycemia indirectly by activation of an inflammatory reaction [29,30,31]. …”

Section: Pathophysiology Of Prediabetes After Strokementioning

confidence: 99%

“…Patients with both impaired fasting glucose and impaired glucose tolerance show both hepatic and muscle insulin resistance and decreased both early- and late-phase insulin responses to oral glucose, which might explain the higher risk in these patients to develop diabetes compared with patients with impaired fasting glucose or impaired glucose tolerance alone [26,32]. There is evidence that insulin sensitivity is impaired after ischemic stroke, possibly due to decreased hepatic insulin receptor expression and upregulation of gluconeogenesis, which can lead to impaired glucose tolerance [31]. …”

Section: Pathophysiology Of Prediabetes After Strokementioning

confidence: 99%

Prediabetes in Patients with Stroke or Transient Ischemic Attack: Prevalence, Risk and Clinical Management

Fonville¹,

Zandbergen²,

Koudstaal³

et al. 2014

Cerebrovasc Dis

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Background: The prevalence of diabetes is emerging worldwide and is an important modifiable risk factor for stroke. People with prediabetes, an intermediate metabolic state between normal glucose metabolism and diabetes, have a tenfold increased risk of developing diabetes compared to those with a normal glucose metabolism. Prediabetes is comprised of impaired fasting glucose and/or impaired glucose tolerance and/or disturbed glycosylated hemoglobin levels. Prediabetes is highly prevalent in nondiabetic patients with transient ischemic attack (TIA) or ischemic stroke and nearly doubles their risk of stroke. This offers new options for secondary stroke prevention. Summary: Several detection methods exist for identifying (pre)diabetes, including fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels. The concordance between these tests is not 100%, and they seem to be complementary. Screening for (pre)diabetes after stroke with fasting plasma glucose levels alone is insufficient, and 2-hour postload glucose and/or glycosylated hemoglobin levels should be determined as well. The prevalence of prediabetes in previously nondiabetic patients with a recent TIA or stroke ranges from 23 to 53%. This high prevalence in the acute phase after stroke can be transient or persistent, representing undiagnosed abnormal glucose metabolism. Impaired fasting glucose and impaired glucose tolerance have different pathophysiological mechanisms, including hepatic insulin resistance and muscle insulin resistance, respectively. Prediabetes seems to be a modest predictor for stroke, but doubles the risk for recurrent stroke. The relation between prediabetes after stroke and functional outcome is still unknown. However, it is most likely that prediabetes is a risk factor for a poor clinical outcome after stroke. There is a growing recognition that patients with prediabetes should be treated more aggressively. Both lifestyle and pharmacological interventions are possible treatment strategies. They are at least equally effective in preventing progression to diabetes. Lifestyle changes are difficult to maintain over a long period. The evidence of pharmacological interventions on stroke or other cardiovascular diseases is limited though and is still subject of several clinical trials. Conclusions: As the prevalence of prediabetes is growing rapidly, prediabetes might become one of the most important modifiable therapeutic targets in both primary and secondary prevention.

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“…As neurons require a constant supply of glucose for normal function, glucose is a major source of energy metabolism for the central nervous system (39). Several studies have documented the effect of glucose-sensing neuropeptides on the development of post-ischemic glucose dysfunction and neuronal damage (22,23), and evidence from a previous in vitro study revealed that glucose itself promotes the development of caspase-dependent apoptosis during re-oxygenation following oxygen and glucose deprivation, and promotes the production of reactive oxygen species, including superoxide anion, hydrogen peroxide and peroxynitrite (40). GK and GKRP have important regulatory roles in glucose metabolism as a glucose sensor.…”

Section: Time Following Ischemia-reperfusion ------------------------mentioning

confidence: 99%

Ischemic preconditioning maintains immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia

et al. 2015

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Ischemic Stroke and Glucose Intolerance: a Review of the Evidence and Exploration of Novel Therapeutic Targets

Cited by 43 publications

References 103 publications

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Prediabetes in Patients with Stroke or Transient Ischemic Attack: Prevalence, Risk and Clinical Management

Ischemic preconditioning maintains immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia

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