Acta Pharmacologica Sinica (2018) 39: 683–694

© 2018 CPS and SIMM All rights reserved 1671-4083/18

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Review Article

The role of KATP channels in cerebral ischemic stroke

and diabetes
Vivian SZETO1, Nai-hong CHEN2, Hong-shuo SUN1,3,4,*, Zhong-ping FENG1,*
1
Departments of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8; 2Institute of Materia
Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; 3Surgery, and 4Pharmacology,
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Abstract
ATP-sensitive potassium (KATP) channels are ubiquitously expressed on the plasma membrane of cells in multiple organs, including the
heart, pancreas and brain. KATP channels play important roles in controlling and regulating cellular functions in response to metabolic
state, which are inhibited by ATP and activated by Mg-ADP, allowing the cell to couple cellular metabolic state (ATP/ADP ratio) to
electrical activity of the cell membrane. KATP channels mediate insulin secretion in pancreatic islet beta cells, and controlling vascular
tone. Under pathophysiological conditions, KATP channels play cytoprotective role in cardiac myocytes and neurons during ischemia and/
or hypoxia. KATP channel is a hetero-octameric complex, consisting of four pore-forming Kir6.x and four regulatory sulfonylurea receptor
SURx subunits. These subunits are differentially expressed in various cell types, thus determining the sensitivity of the cells to specific
channel modifiers. Sulfonylurea class of antidiabetic drugs blocks KATP channels, which are neuroprotective in stroke, can be one of the
high stoke risk factors for diabetic patients. In this review, we discussed the potential effects of KATP channel blockers when used under
pathological conditions related to diabetics and cerebral ischemic stroke.

Keywords: potassium channels; KATP channels; KATP channel blockers; sulfonylurea; stroke; diabetes

Acta Pharmacologica Sinica (2018) 39: 683–694; doi: 10.1038/aps.2018.10; published online 19 Apr 2018

Introduction tissue plasminogen activator (rtPA) can be used during a lim-

Stroke and diabetes are currently the most common causes of ited window of time immediately following the stroke insults
death and the leading causes of chronic disability in the world. to dissolve the blood clot and reduce the severity of the stroke
Diabetes is associated with higher risk of stroke. Both stroke damage in the brain, however, there is currently no other
and diabetes cause significant social and economic impacts effective treatment for stroke. Therefore, taking prophylactic
worldwide. Thus, further understanding of stroke in diabetes measures is the most effective strategy.
can help to prevent occurrences and develop new therapeutic Diabetes mellitus is a group of metabolic disorders with
targets, which are priorities for stroke research. persistent hyperglycemia that may be fatal if not managed
Stroke is characterized by inadequate oxygen, blood and appropriately. There are three main types of diabetes includ-
nutrient supply to the brain due to a vascular event, either a ing type 1, type 2 and gestational diabetes. Persistent hyper-
cerebrovascular clot or rupture. There are three main types glycemia in diabetes mellitus is caused by hypoinsulinemia
of stroke, ischemic (commonly caused by vessel blockage), and/or insulin insensitivity as a result of pancreatic beta-cell
hemorrhagic (caused by vessel rupture) and transient ischemic failure or periphery insulin resistance, diabetes is as a result
attack (caused by temporary vessel blockage). Poor blood of both genetic and environmental factors[1]. Serious long-
flow or bleeding in the brain due to stroke can result in neuro- term diabetic complications include stroke, heart disease, foot
nal death and rapid loss of cognitive and physical functions, ulcers, nephropathy, retinopathy and neuropathy. Diabetes and
which may be permanent. In ischemic stroke, recombinant its common comorbidities include hypertension, high blood
cholesterol, atherosclerosis, atrial fibrillation and obesity,
*To whom correspondence should be addressed.
all of which independently contribute to increasing the risk
E-mail hss.sun@utoronto.ca (Hong-shuo SUN);
for stroke[2]. As many as 43% of patients admitted for acute
zp.feng@utoronto.ca (Zhong-ping FENG) ischemic stroke have undiagnosed diabetes[3]. Diabetes is con-
Received 2017-11-22 Accepted 2018-02-19 sidered as a major independent risk factor for stroke that is
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684 Szeto V et al

consistently observed in multiple racial backgrounds[4–6]. Both Cerebrovasculature and endothelia

ischemic and hemorrhagic stroke risk are demonstrated in The vasculature is essential to neuronal function as it is
diabetics[7,8], however this review is focused on ischemic stroke responsible for delivery of nutrients and removal of metabo-
which is more common in diabetics. lites. Any impairment/damage to vasculature due to diabetes
can have detrimental effects on neurological health especially
Diabetes and cerebral ischemic stroke in the event of ischemic injury. Prolonged hyperglycemia
Diabetes increases stroke risk through a multitude of different induces vascular changes, ranging from microvascular (reti-
mechanisms including high HbA1c, microvascular compli- nopathy) to macrovascular (atherosclerosis) and leads to
cations and low HDL cholesterol[9]. Under Medicare in the hypoperfusion/hypoxia. Diabetes leads to endothelial dys-
United States, one stroke event costs $22,657 initially and up function causing poor structural integrity of vessel walls,
to $2488 per month thereafter for up to a year[10]. A projected arterial stiffening causing increase risk for vessel damage and
439 million individuals will suffer from diabetes by 2030 and systemic inflammation ultimately leading to atherosclerosis
with it carry dramatically higher risks for limb amputations, (risk factor for stroke) and stroke[19]. Hyperglycemia reduces
vision loss, heart disease and stroke complications[11]. With- available NO vasodilator, reducing perfusion to brain, inten-
out an effective treatment to reverse stroke damage, preven- sifying inflammatory response and edema further increasing
tion remains the best option. Diabetes induces changes in all cell death post-stroke [34,37]. Further, STZ-diabetes induces
aspects of the neurovascular unit, increasing vascular disease S-glutathionylation of Kir6.1, reducing number of functional
risk and impairing functional recovery from ischemic events. KATP channels, impairing vasodilation in heart, kidney and
Presently, the most effective preventative measures are inten- mesenteric rings. Similar studies have not been done to con-
sive blood glucose, blood pressure and blood lipid control[12–14]. firm effects in cerebrovasculature[38,39]. In ischemia conditions,
Hyperglycemia and hypoinsulinemia are detrimental to brain intranasal insulin injections have been proven beneficial for
function. Acute and long-term complications can be mini- acute events[40,41]. In addition, hyperglycemia induces down-
mized with adequate glycemic control through diet and exer- regulation of microRNA223 and -146a leading to platelet
cise, insulin injections and/or oral medications. Diabetes and activation and increased risk for stroke in diabetic patients[42].
hyperglycemia cause more severe stroke outcomes[15–18], and Another diabetic complication, ketoacidosis, increases stroke
therefore glycemic control is extremely important for stroke risk and is known to induce acute cerebral infarction [43–46].
prevention. The correlation between hyperglycemia, diabetes, Diabetic ketoacidosis causes systemic inflammation disrupt-
increased stroke risk and poorer post-stroke outcomes is very ing vascular endothelia structure and tight-junction function,
well established[19–27]. coagulopathy, increased hemorrhagic and thrombotic risk
and impaired cerebral autoregulation [45–48]. When diabetic
Neuron ketoacidosis is complicated with hypertension and/or hyper-
Diabetes is associated with many different types of neuropa- lipidemia (commonly present in diabetic patients), stroke risk
thy. Prolonged hyperglycemia causes periphery (impaired is further increased[43,44]. Diabetes induces pathological neo-
sensation in extremities), autonomic (disrupted autonomic vascularization contributing to retinopathy, however diabetes
control), proximal (pain and weakness in limbs) and focal neu- can impair neovascularization and cause regression in other
ropathy (sudden weakness of one nerve). Most diabetic neu- vascular beds like the brain[49]. Typically, angiogenic genes are
ropathies are closely linked to microvascular injury, however unregulated with stroke shortly after the event as angiogen-
there are various suggested mechanisms forming a direct link esis after stroke greatly improves functional recovery[50,51]. In
from hyperglycemia, hypoinsulinemia and insulin resistance diabetic condition after stroke, neoangiogenesis is impaired
to nerve damage. High levels of glucose can cause excessive but improved with more intensive glucose control and blood
influx of sugar alcohols, excessive free radical stress, loss of pressure control[52–56]. In conclusion, diabetes induces vascular
cytoskeletal proteins, and lack of up-regulation of axon repair changes that are conducive of stroke events and poorer stroke
proteins upon nerve injury[28–32]. In the case of diabetic stroke, recovery.
hyperglycemia overloads anaerobic energy production caus-
ing stress on neurons and can exacerbate any calcium imbal- Glial cells
ances and ROS accumulation therefore leading to increased Glial cells are the most abundant cell type in the brain; the
cell death upon ischemic injury[33]. Further, stroke in diabetes three main types are astrocytes, oligodendrocytes and microg-
induces epigenetic down-regulation of neuron-specific eno- lial cells. Although they do not directly participate in synaptic
lase and neuronal nitric oxide synthase as compared to non- signaling they have important supportive functions like main-
diabetic stroke[34]. Neuron-specific enolase is implicated in taining the necessary chemical environment for proper signal-
synapse formation and its release into serum is a biomarker ing, myelination of axons to assist axon potential conductance
for stroke [35,36] . Post-ischemic hyperglycemia enhances and mediating response to brain injury. As compared to the
sodium-glucose transporter 1 and exacerbates neuronal dam- non-diabetic stroke model mice, the diabetic stroke model
age[33]. Hence, strict glycemic control in diabetes reduces the showed epigenetic down-regulation of connexin-43, GFAP
incidence of diabetic neuropathy. and CD11b in glial cells[34]. Connexin-43 is a component of
astrocyte gap-junction, essential for gap-junction structure and

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function. In stroke, connexin-43 expression and transloca- SUR2A subunits, in smooth muscles SUR2B, in adipose tissue
tion is disrupted and over-expression can stabilize astrocytes, Kir6.1/SUR2B, and in the brain neurons mostly Kir6.2/SUR1
rescue astrocytes from stroke’s detrimental effect and promote while in astrocytes only Kir6.1/SUR1 and 2[71–75]. KATP channels
neuronal recovery [57]. GFAP promotes axonal remodeling were first described in isolated ventricular myocytes of the
and motor behavioral recovery post stroke and is important guinea pig[76], and have been studied for their role in diseases
in maintaining blood brain barrier properties and white mat- from diabetes and hyperinsulinemia to cardiac arrhythmias
ter vascularization[58–60]. This is consistent with reports that and cardiovascular disease. KATP channels mediate insulin
the blood brain barrier has compromised permeability under secretion in pancreatic islet beta cells, and controlling vascular
diabetic condition[61]. CD11b is a well-established proinflam- tone[77]. Under pathophysiological conditions, KATP channels
matory cytotoxicity and phagocytosis marker [62]. In stroke play cytoprotective role in cardiac myocytes and neurons dur-
condition it is usually up-regulated for microglial activation[63]. ing ischemia and/or hypoxia[78–81].
CD11b down-regulation in diabetic stroke is difficult to inter-
pret without more spatioresolution as targeted phagocytosis Neuroprotective effect of KATP channels in stroke
may assist in early synaptic remodeling and containment In a stroke or an ischemic event, there is a shortage of oxy-
of injury[64]. Additionally, the role of microglial in stroke is gen and/or nutrient delivery and hence reduction of cellular
complex in that microglial activation can result in a range of ATP. Therefore, KATP channels are activated by the rise in
phenotypes both pro- and anti-inflammatory and phagocyto- ADP/ATP ratio. This increase in KATP channel activity and
sis can attenuate inflammation but also cause more neuronal hyperpolarization during an ischemic event is thought to be
damage by phagocytosis of viable neurons[65,66]. Therefore, the important for protecting the cells from cell death and excito-
role of microglial in stroke in presence of diabetes needs to be toxicity[82,83]. In ischemic conditions, activation of KATP chan-
further studied. Glutamate uptake by astrocytic glutamate nels underlie many cardioprotective mechanisms[78]. Alpha-
transporters is important to maintain a low extracellular con- lipoic acid, diosgenin, estrogen, atorvastatin, vitamin C and
centration to avoid excitotoxicity and neuronal damage. In the angiotensin III have all been implicated as therapeutic agents
case of neuronal injury by stroke, glutamate is exocytosed at for purpose of cardioprotection and suggested to function via
great quantities causing excitotoxicity, ion imbalance and neu- KATP channels[84–90]. Aside from these cytoprotective agents,
ronal death. STZ-diabetic mice show no change in glutamate KATP channels are implicated in ischemic preconditioning in
transporter (GLT-1 and GLAST) levels despite others reporting the heart[91]. Ischemic preconditioning is when one or several
decrease in glutamate uptake in STZ-diabetic mice indicating intermittent periods of ischemia disconcertingly results in pro-
a possible decrease in functionality of protein[67]. This suggests tection against tissue damage by a subsequent and sustained
that although diabetes and prolonged hyperglycemia does not ischemic injury[79]. KATP channel activation prior to ischemic
affect the number of glutamate transporter, it may be impair- event mimics the effects of ischemic preconditioning[78,80,92].
ing transporter function. Diabetes also reduces oligodendro- Similarly, in the brain KATP channels play a role in ischemic
cyte progenitor cell proliferation and survival under chronic tolerance in stroke, conferring neuroprotection[81]. In diabetic
ischemia which both correlated with more severe white mat- brain, expression of Kir6.2 was significantly reduced, however,
ter injury[68]. Diabetes results in more demyelination during whether SUR1 expression was affected remained inconclu-
stroke and less remyelination in the recovery of the ischemic sive[93].
penumbra[69]. In conclusion, the diabetic condition can impair
glial function in turn compromising neuronal health and Neuronal KATP channels
impair glial reaction to ischemic injury thereby exacerbating KATP pore forming subunits Kir6.1 and Kir6.2, as well as their
stroke injury. regulatory subunits SUR1 and 2B, are expressed at high levels
in the brain (cortical and hippocampal areas)[73,74,81,94,95]. Neu-
KATP channels ronal KATP channels play an important role in regulating neu-
Potassium channels are ubiquitously expressed ion chan- ronal excitability and spontaneous firing in neurons including:
nels, present across essentially all cell types[70]. Opening of K+ cholinergic basal forebrain neurons, expiratory neurons, ento-
channel leads to an efflux of K+ ions, hyperpolarizing the cell. rhinal layer 3 cortical neurons, substantia nigra neurons, thala-
Adenosine triphosphate (ATP)-sensitive K + (KATP) channels mocortical neurons[96–100]. Neuronal KATP channels also play a
conduct weak inward rectifier potassium current and belong critical role in glucose homeostasis at the hypothalamic level
to the Kir superfamily of K+ channels. KATP channels are com- by regulating the secretion of glucagon and catecholamines[101].
posed of 4 pore-forming subunits (Kir6.1 or Kir6.2 encoded by In neuronal monocultures, pretreatment with diazoxide, a of
KCNJ8 and KCNJ11, respectively) and 4 regulatory sulfonyl- KATP channel opener, induced delayed preconditioning against
urea receptor SUR ATP-binding cassettes subunits (subfamily oxygen glucose deprivation (OGD) and reduced cell death.
C: SUR1, SUR2A or SUR2B). KATP channels are inhibited by These effects of diazoxide were suggested via inhibition of
ATP and activated by Mg-ADP, allowing the cell to couple succinate dehydrogenase not mitochondrial KATP channel[102].
cellular metabolic state (ATP/ADP ratio) to electrical activity Hippocampal neuron culture studies suggest that diazox-
of the cell membrane. In pancreatic beta cells Kir6.2/SUR1 ide decreases neuron apoptosis by preventing cytochrome c
are the major subunits expressed, in cardiac myocytes Kir6.2/ release, increasing Bcl-2 release and inhibiting Bax association

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686 Szeto V et al

with mitochondria[103]. In a study comparing KATP channel ischemic preconditioning in humans[123]. Before an ischemic
blocker and activator, blocker increased neuronal death in event, KATP mediated ischemic preconditioning of endothelial
OGD of cultures while activator conferred neuroprotection[104]. and during an ischemia event, vascular smooth muscle KATP
Activation of KATP channels is neuroprotective in both focal activation may be favourable as vasodilation could increase
and global ischemia in vivo models, and the in vitro results perfusion to the tissue and be therapeutic. In pathological
suggest these effects are mediated at least in part by neuronal conditions like hypertension (a stroke risk factor), the vaso-
KATP channels [81,94,95,105]. dilation response to KATP channels is impaired at large cere-
bral arteries and microvessels (much like with KATP channel
Glial KATP channels blocker) and may predispose brain to ischemia and stroke[124].
Astrocytes can provide protection in the event of ischemic Therefore blockade of vascular K ATP channels can worsen
events by supporting blood brain barrier integrity, reduc- hypertension and reduces blood flow which may predispose
ing glutamate excitotoxicty and donation of mitochondria to tissues to larger infarctions in the event of stroke[125]. In STZ
neurons during recovery[106]. Glutamate uptake by astrocytic diabetic model Kir6.1 S-glutathionylation reduces number of
glutamate transporters maintains low extracellular concentra- functional KATP channels, impairing vasodilation in heart, kid-
tion to avoid excitotoxicity. Selective activation of mitochon- ney and mesenteric rings[38,39]. Whether the neuroprotective
drial KATP channels in astrocytes increases glutamate uptake effects of KATP channel activators are through neuronal, glial
in culture which could confer an protective advantage[107]. and/or vascular channels is not fully understood. Because
However, there has not been in vivo confirmation of these find- glial cells and the vasculature play an important role in stroke
ings. In astrocyte monocultures, the channel opener diazoxide pathobiology, understanding the role of KATP channels in glial
pretreatment induced delayed preconditioning against oxygen and endothelial cells could further explain the detrimental
glucose deprivation (OGD) blocking cell death as did in neu- effects of KATP channel blocking in ischemic stroke and the
ronal cultures suggesting that the protective effects observed neuroprotective effects of activation.
in vivo may be in part due to astrocytic KATP channels[108]. In
primary microglia cultures, KATP channel opener can prevent KATP channels in in vivo stroke models
rotenone-induced microglia activation and neuroinflamma- Middle cerebral artery occlusion (MCAO) of rodents is a
tion. In BV2 microglia cell line, the channel blocker gliben- commonly used animal model for focal stroke. KATP channel
clamide increased reactive microglia, phagocytic capacity and opener diazoxide reduced neuronal damage after MCAO[126]
TNFα release in response to pro-inflammatory signalling[109,110]. and also induced delayed preconditioning against transient
Activated microglia at early phases of stroke was correlated focal cerebral ischemia and reduced infarction volumes[127] in
with neuroprotection[110]. Currently, it is not clear whether rats. Similarly, activation of mitochondrial KATP channels by
Kir6.x channel subunits are affected by diabetes, however BMS-191095 reduced total infarction volume in rats undergone
hyperglycemia can reduce expression and function of astro- MCAO[127]. Consistent with these observations, KATP channel
cytic ATP-sensitive Kir4.1 channels in parallel with a decrease blocker tolbutamide increased infarction volume and neuro-
in glial glutamate level, suggesting a role of astrocytic potas- logical deficits in MCAO model in mice, while KATP channel
sium channels in poor stroke prognoses[111]. Since diabetes opener provided neuroprotection[104]. A separate study using
induced S-glutathionylation of Kir6.1 is likely not limited to 5-hydroxydecanoate as antagonist and diazoxide as agonist
vasculature, the reduction of functional Kir6.1 subunit con- in MCAO rat model showed these effects were conserved[128].
taining KATP channels in diabetic condition could exacerbate These findings were further confirmed in genetic knockout
ischemic stroke-induced brain damage. Astrocytes and oligo- mouse model, indicating endogenous cortical KATP channel
dendrocytes ubiquitously express Kir6.1 and SUR1 which are activation provides protection against cerebral ischemic stroke
activated under ischemic condition, however the specific func- induced infarction and neurological deficits[129,130]. In trans-
tion and/or expression of the glial channels in diabetes have genic mice overexpressing Kir6.2 channel, the animals exhib-
not been thoroughly studied[112–114]. ited strong neuroprotection against hypoxic-ischemic injury[131].
There are some conflicting accounts from studies using gliben-
Vascular KATP channels clamide and glyburide, the second generation of sulfonylurea
KATP channels are expressed in vascular smooth muscle[115,116], class KATP channel blocker. Used alone or in combination with
likely Kir6.1 and SUR2B subunits [117,118]. Vasodilators (e.g. hypothermia, glibenclamide improved neurological outcome
adenosine, calcitonin gene-related peptide and beta-agonists) after MCAO in rats and 30 day survival were improved[132–134].
and –constrictors (angiotensin II, endothelin-I and vasopres- SUR1 subunit can couple with non-selective cation chan-
sin) increase or decrease KATP channel activity, respectively, nel, transient receptor potential melastin 4 (TRPM4) channel,
via PKC pathways[115,119–121]. KATP channels in the vasculature which is involved in development of cerebral edema in brain
regulate vascular tone and blood flow to all organs includ- injury[135–137]. It is possible that glibenclamide affects the SUR1-
ing the brain. Vascular muscle KATP channel activation causes TRPM4 complexes, thus reduced cerebral edema and swelling
vasodilation by controlling arterial diameter[122]. In healthy following stroke[138–141]. Overall, animal studies suggest KATP
volunteers gilbenclamide (SUR class K ATP blocker) blocked channel openers reduce and the channel blockers increase
while diazoxide (KATP channel opener) mimicked endothelial brain damage. Further studies are required to understand the

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Figure 1. KATP channels are neuroprotective and sulfonylurea use can exacerbate ischemia-induced brain damage. In the pancreatic β cells, KATP
channels serve as a metabolic sensor to post-prandial glucose metabolism. The closure of KATP channels depolarizes cell membrane, activates voltage-
gated calcium channels (VGCCs), and thus leads to insulin release. In the diabetic patients, sulfonylureas can be used to block KATP channels and
increase insulin release. In an ischemic neuron, the reduction in ATP:ADP ratio opens KATP channels, lowering membrane potential and stabilizing the
membrane, thus reducing cell excitotoxicity. In the diabetic patients using sulfonylureas, the neuroprotective effects of KATP channels are abolished.

mechanisms underlying the differential effects of sulfonylurea paired potassium channel are highly sensitive to sulfonylurea
class KATP channel blockers on stroke severity. inhibition and diazoxide activation [143]. In special circum-
There is abundant evidence that KATP channel activity is stances, PIP2 can uncouple Kir6.2 from sulfonylurea bound
neuroprotective in ischemic events. Not surprisingly, there SUR1, producing SU-independent current[71]. Mutations that
are a plethora of patents involving K ATP channels and neu- alter K ATP channel activity are commonly seen in patients
roprotection[142]. Activation of KATP channels hyperpolarizes with neonatal diabetes, hyperinsulinemia and developmental
neurons, which can prevent excitotoxicity, stabilize membrane delay-epilepsy-neonatal diabetes (DEND syndrome)[144–147].
potential, reduce ionic imbalance and protect neurons from Specifically, mutations in SUR subunit are associated with dia-
ischemia-induced death[129]. A schematic diagram is shown in betes[148]. KATP channels and SUR modulatory subunits act as
Figure 1. key drug targets for diabetes hyperglycemic control. SUR sub-
unit renders KATP channels sensitive to sulfonylureas. Sulfo-
KATP channel blockers in diabetes treatment nylureas, KATP channel blockers, are the oldest class of hyper-
A prime example of KATP channels coupling metabolism to glycemic controlling drugs. Sulfonylureas reduce MgADP
electrical activity is in pancreatic beta cells. Glucose metabo- binding and efficacy of ADP-induced opening, and results in
lism causes depolarization of the cell linking to insulin secre- closure of KATP channel[149]. Effectively, sulfonylureas block
tion. When glucose enters via GLUT2 transporter and it is KATP channel activity and induce insulin release (Figure 1).
metabolized by glucokinase resulting in increase in ATP/ KATP channels are a major drug target in type 2 and neonatal
ADP ratio. ATP induces KATP channel closure causing beta cell diabetes. Closure of KATP results in depolarization and insulin
depolarization, voltage-gated calcium channel activation and secretion in pancreatic β cells (Figure 1). SUR blockers can
leading to calcium-dependent insulin release (Figure 1). SUR be categorized into two sets, drugs that block both SUR1 and
subunit facilitates KATP current via its ADP-binding. SUR1 SUR2: gilbenclamide, glimepiride, repaglinide, meglitinide

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688 Szeto V et al

and those that are SUR1 specific: tolbutamide, ngliclazide sulfonylureas found no appreciable increase in all-cause mor-
and nateglinde [150]. Gliclazide and tolbutamide inhibition tality, stroke or myocardial infarction with prescribed second
is readily reversible while gilbenclamide, glimepiride and or third generation sulfonylureas[168]. To move forward, new
repaglinide exhibit a much slower reversibility. Gilben- studies in relationship between sulfonylurea use and cere-
clamide binds to SUR1 at two sites, thus perhaps rendering brovascular mortality, as well as all-cause mortality should
slow dissociation. This is in line with the similar structure specify individual sulfonylureas used by each participant.
between gilbenclamide and glimepiride[150]. Sulfonylurea class Sulfonylureas target a fundamental step of insulin secre-
anti-diabetic drugs and its derivatives are used in diabetes tion and are effective in treating diabetes with diverse genetic
mellitus to stimulate insulin release and control blood glucose. causes, thus are useful where genetic testing is not readily
Clinically, they are classified into three generations: the sec- available[170]. The heterogeneity of their effects on stroke might
ond and third generation sulfonylureas are generally safer (i.e. be in part related to genetic polymorphisms at the cytochrome
lower risk of hypoglycemia, cardiovascular events) than the P450 2C9 (CYP2C9) gene, encoding the enzyme that primar-
first generation. Sulfonylureas have potent glucose lowering ily metabolizes sulfonylureas[171] or at the ABCC gene sites.
effects and newer oral antidiabetics (including metformin, thi- Individual differences affecting how the body processes sulfo-
azolidinediones, exenatides, and symlins) show lower risk of nylureas to how the sulfonylureas act on the targets remained
inducing hypoglycemia, thus are a popular choice in western- to have a large impact. In line with these possibilities, efforts
healthcare. However first generation of sulfonylureas remains could be made in pharmacogenetics to determine patients with
the key in diabetes care in developing countries [151,152]. CYP2C9 mutations (CYP2C9*3/*3) which prolong effects of
sulfonylureas in the body[171]. This poses a great challenge as
Cerebrovascular safety of SUR blocking anti-diabetic the areas that have fast growing diabetic populations and tend
drugs and future directions toward sulfonylureas are unlikely to have access to genetic
The American College of Physicians (ACP) in clinical practice screening before treatment. In developing countries with lim-
guideline updates for oral pharmacological treatment of T2D ited access to genetic testing and limited resource, affordable
states that sulfonylureas are associated with weight gain and and reliable treatments like sulfonylureas are highly valuable.
more episodes of hypoglycemia than metformin[153]. However, According to the Association of Physicians of India, sulfonyl-
there is low quality and inconsistent evidence to suggest sulfo- ureas are prescribed as their first line for non-obese diabetic
nylureas alone or metformin combination treatment increases patients by most of doctors[172]. Given the role of KATP channels
cardiovascular risks/all-cause mortality as compared to in neuroprotection, there is a concern for the safety of sulfo-
metformin treatment of T2D. A recent meta-analysis of sulfo- nylureas usage in this population with increased risk of stroke.
nylurea treatment of diabetes and stroke risk summarizes 17 The pharmacokinetic and pharmacodynamic profiles of
randomized controlled trials concluded with high confidence each sulfonylureas are different. Prescribing sulfonylureas
that sulfonylureas monotherapy or combination therapy with lower permeability to the brain or shorter half-life could
increases the number of stroke events in diabetic patients as mitigate their effects on stroke risk while achieving insulin
compared to comparator drug or placebo group[104,154]. Since and glycemic targets. Further, sulfonylureas display almost
then there have been other reviews on cardiovascular events complete serum protein binding (90%–99%) once absorbed
and anti-diabetic agents, however no new analysis focus- and their clearance is hindered by renal impairment which is
ing on stroke and sulfonylureas[155–159]. In line with the ACP, common in diabetics. Only tolbutamide has been studied for
other independent reviews including Cochrane review of 301 its ability to across the blood-brain-barrier and have a minimal
clinical trials conclude that sulfonylurea safety in treatment serum accumulation[173,174]. Under diabetic or stroke condi-
of diabetes is still unclear[157,158,160]. As for stroke risk, studies tions, the blood-brain-barrier integrity is damaged and its per-
of effects of sulfonylureas on stroke severity and recovery are meability to drugs is altered[175], and thus detailed understand-
incomplete[161–164]. Despite new evidences emerging, due to ing of the levels of individual sulfonylureas in brain under
many conflicting accounts in both animal and human studies, these pathological/pathophysiological conditions should be
cerebrovascular safety of sulfonylurea remains controver- further explored.
sial[161,163,165–168].
Many sources could contribute to the heterogeneity among Conclusion
the studies. For instance, the wide variety of sulfonylureas KATP channels play important roles both in physiologic and
has been used in studies or prescribed in clinics (different pathophysiologic settings, from insulin secretion to cyto/neu-
generations, short, intermediate or long acting). Clinical/ roprotection. Activation of KATP channels in ischemia and/or
epidemiological studies that indicate the specific sulfonylurea hypoxia can provide neuroprotection to stroke and hypoxia.
subgroup analysis are insufficient. Sulfonylurea subgroup Diabetes is one of the major risk factors for stroke and leads
analysis by generation has been employed in terms of evaluat- to more severe stroke outcomes particularly if hyperglycemic
ing risk of hypoglycemia however cardiovascular and cere- management is inadequate. Sulfonylurea class of antidiabetic
brovascular risk are newer areas in comparison[169]. Although drugs blocks K ATP channels which are neuroprotective in
there has been no report comparing the types of sulfonylurea, stroke, and can be one of the high stoke risk factors for dia-
one meta-analysis that excluded studies using first generation betic patients. The first generation of sulfonylurea is currently

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