Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Special Issue: The Year in Diabetes and Obesity

Review

Diabetes, stroke, and neuroresilience: looking beyond

hyperglycemia
Matthew J. Krinock and Neel S. Singhal
Department of Neurology, University of California - San Francisco, San Francisco, California

Address for correspondence: Neel S. Singhal, MD, PhD, Department of Neurology, University of California – San Francisco,
555 Mission Bay Blvd S., MS3118, San Francisco, CA 94158. neel.singhal@ucsf.edu

Ischemic stroke is a leading cause of morbidity and mortality among type 2 diabetic patients. Preclinical and trans-
lational studies have identified critical pathophysiological mediators of stroke risk, recurrence, and poor outcome
in diabetic patients, including endothelial dysfunction and inflammation. Most clinical trials of diabetes and stroke
have focused on treating hyperglycemia alone. Pioglitazone has shown promise in secondary stroke prevention for
insulin-resistant patients; however, its use is not yet widespread. Additional research into clinical therapies directed
at diabetic pathophysiological processes to prevent stroke and improve outcome for diabetic stroke survivors is
necessary. Resilience is the process of active adaptation to a stressor. In patients with diabetes, stroke recovery is
impaired by insulin resistance, endothelial dysfunction, and inflammation, which impair key neuroresilience path-
ways maintaining cerebrovascular integrity, resolving poststroke inflammation, stimulating neural plasticity, and
preventing neurodegeneration. Our review summarizes the underpinnings of stroke risk in diabetes, the clinical
consequences of stroke in diabetic patients, and proposes hypotheses and new avenues of research for therapeutics
to stimulate neuroresilience pathways and improve stroke outcome in diabetic patients.

Keywords: diabetes; stroke; neuroprotection; endothelial; neuroinflammation; neuroplasticity

Introduction reducing patients’ risk and severity of the first-time

stroke, as diabetic patients with adequate glycemic
Stroke is one of the most predominant causes of
control have lower rates of recurrent stroke.7,8 Of
morbidity and mortality in the world. In the United
even greater importance for individual diabetic
States, approximately 800,000 Americans per year
stroke patients is that pathophysiological features
suffer a stroke, leading to over $30 billion in hospital
associated with diabetes, such as hyperglycemia,
and lost productivity costs per year.1 Strokes cause
endothelial dysfunction, poor collateral circula-
sudden paralysis or motor impairments, speech dis-
tion, and immune dysregulation, interfere with pro-
turbances, and/or loss of vision, among other neu-
cesses promoting brain cell survival and neuro-
rological symptoms. This is most often due to an
logical recovery during and following a stroke. In
interruption of blood flow caused by an embolism
this review, we outline the clinical implications
to arteries supplying the brain. Aging, hyperten-
of T2D in stroke. We focus on ischemic stroke,
sion, diabetes, smoking, and hypercholesterolemia
the most common cerebrovascular manifestation of
are the most important risk factors for stroke. Dia-
diabetes, which is associated with even higher mor-
betes increases an individual’s risk of stroke by
bidity among patients with diabetes. We also explore
1.5–3-fold.2–4 Importantly, the increasing preva-
the mechanisms linking the two diseases and sug-
lence of type 2 diabetes (T2D) is a key factor under-
gest research avenues to improve stroke preven-
lying increasing rates of stroke in patients under
tion, recovery, and neuroresilience in patients with
65 years old.2,5,6 Controlling diabetes is crucial to
diabetes.
doi: 10.1111/nyas.14583
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences. 1
Diabetes and stroke Krinock & Singhal

Figure 1. Ischemic stroke subtypes. (A) Large-vessel occlusion (LVO) stroke. The left panel shows a brain diffusion–weighted
(DW) MRI image from a patient with newly diagnosed atrial fibrillation suffering from a large left hemisphere infarction due
to middle cerebral artery (MCA) occlusion. The right panel schematic illustrates that LVO can quickly lead to an area of core
infarction as well as a larger area of ischemic but viable brain tissue termed the penumbra. Patients with a large penumbra benefit
from endovascular thrombectomy (EVT) as an acute stroke treatment. Patients with poor collaterals, a complication of diabetes,
may suffer larger core infarct growth over time and benefit less from EVT. (B) Lacunar stroke. The left panel demonstrates a DW-
MRI image from a patient with untreated T2D presenting with acute weakness due a lacunar stroke in the internal capsule. The
right panel schematic illustrates that lacunar infarctions result from small-vessel atherosclerotic disease in end arterioles without
collateral flow causing a smaller “lacunar” infarction, often in brain regions necessary for motor control.

Diabetic patients are predisposed to stroke
and suffer worse outcomes
In the United States, the majority of strokes
are ischemic in nature (87%), with hemorrhagic
strokes, often associated with hypertension, com-
prising the remaining balance.1 Ischemic strokes
can be further classified into large- or small-vessel
strokes (Fig. 1). Large-vessel strokes can lead to
profound neurological deficits and even death due
to large areas of brain infarction from embolic
occlusion of the carotid or proximal cerebral

2 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal
arteries. This is often the result of cardioembolism
from atrial fibrillation, structural heart disease,
atherosclerotic disease, or a hypercoagulable state.
Strokes resulting from vascular disease of end arte-
rioles result in “lacunar” infarctions of deep brain
structures. This includes brain regions supplied by
end arterioles, such as the lenticular nucleus, inter-
nal capsule, thalamus, and pons.9,10 These “small-
vessel strokes” are typically associated with small
areas of brain infarction (often <1.5 cm) but result
in highly morbid deficits due to their localization
near prominent motor tracts. Lacunar strokes are
usually associated with chronic hypertension or dia-
betes and are characterized by pathological thick-
ening of the arterial media by fibrinoid deposition
(lipohyalinosis) or obstruction of penetrating end
arteries by intimal plaques.10,11
There are clear differences in stroke patterns in
patients with diabetes. Patients with diabetes have
a higher proportion of ischemic stroke compared
with hemorrhagic strokes. Epidemiological studies
are mixed as to whether the risk of hemorrhagic
stroke is elevated in diabetic patients compared
with nondiabetic patients.3,4 Intracranial stenoses
are more common in patients with diabetes and
are proportional to its severity.12,13 Interestingly,
among diabetic patients suffering ischemic stroke,
lacunar stroke may be more prevalent than large
vessel stroke.14 This may be particularly impact-
ful for diabetic patients suffering from stroke, as
the risk of lacunar stroke recurrence is higher than
with other stroke types, as is the risk of devel-
oping cognitive impairment or dementia.15,16 As
with numerous other health outcomes, diabetes
negatively impacts the care of hospitalized stroke
patients. Diabetic patients suffering a stroke experi-
ence increased length of hospital stay, worse func-
tional outcomes, and have a higher risk of stroke
recurrence.17–19 Diabetics also have two-fold higher
1-year mortality compared with nondiabetic stroke
patients.7,20 Glycemic control is extremely critical to
secondary stroke prevention, as each 1% increase in
hemoglobin A1c increases the odds of death follow-
ing a stroke by approximately 33%; however, tight
glycemic control does not completely abate the ele-
vated risk of stroke recurrence in diabetic patients.21
Diabetes may also be an important determi-
nant of the efficacy of new and highly efficacious
acute ischemic stroke treatments for large-vessel
occlusion (LVO). The mainstay of acute ischemic
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Diabetes and stroke
stroke treatment since 1995 has been recanaliza-
tion of blocked arteries with tissue plasminogen
activator.22 Over the last 6 years, there has been
a paradigm shift with the advent of mechani-
cal endovascular thrombectomy (EVT) for patients
with occlusion of large vessels presenting with
favorable imaging characteristics indicative of brain
tissue that is likely to be salvaged by reperfusion.23
Although this has revolutionized acute stroke treat-
ment, diabetic patients with LVO treated with
EVT achieve favorable neurological outcomes at
3 months only 35% of the time, compared with
50–55% for nondiabetic patients.24,25 This does not
appear to be related to differences in EVT reper-
fusion success. The reasons for this marked dis-
crepancy are not fully understood but may include
poor collateral circulation, comorbid intracranial
atherosclerotic disease, increased susceptibility to
cell death during ischemia and reperfusion, and
impaired recovery mechanisms. Intriguingly, the
efficacy of EVT may unmask further disparity in the
outcomes of nondiabetic compared with diabetic
patients as nearly two-thirds of diabetic stroke sur-
vivors will still suffer permanent and severe func-
tional disabilities. Thus, a more detailed under-
standing of the mechanisms underlying poor stroke
outcomes in diabetic patients is essential. We pro-
pose that further understanding how the systemic
consequences of diabetes, including endothelial
dysfunction and inflammation, affect stroke risk
and neurorecovery pathophysiology will lead to
important new insights to promote resilience and
improve stroke outcomes in diabetic patients.
Physiological mechanisms mediating
stroke risk and poor outcomes in diabetes
Diabetes increases cardiovascular disease risk,
including stroke, through systemic metabolic and
inflammatory effects that alter the structure and
function of blood vessels and modulate immune
function. Over time, arteries, arterioles, and cap-
illaries become increasingly stiff, tortuous, and
narrowed as a result of diabetes.26 Atheroscle-
rosis and thrombogenesis are accelerated, and
physiological processes critical to endogenous
neuroresilience and recovery, such as cerebral
vasoreactivity, blood–brain barrier (BBB) perme-
ability, neuroplasticity, and neuroinflammation, are
compromised (Fig. 2).
3
Diabetes and stroke Krinock & Singhal

Figure 2. Diabetes exacerbates stroke injury and impairs neuroresilience. The temporal cellular and physiological events fol-
lowing stroke are altered by diabetic pathophysiology. (A) In particular, diabetic patients suffer increased neuronal injury
and degeneration due to increased susceptibility to bioenergetic failure, blood–brain barrier (BBB) dysfunction, and increased
M1 proinflammatory microglial/macrophage polarization. (B) Diabetes also reduces endogenous compensatory and neurore-
silience mechanisms, including increased cerebral blood flow from collateral circulation compensation, anti-inflammatory M2
microglial/macrophage polarization, and neural plasticity.

Although many clinical studies and trials sur-
rounding stroke and diabetes focus on hyper-
glycemia, endothelial dysfunction coupled with
inflammation has emerged as central to the cascade
of pathophysiological events predisposing diabetic
patients to stroke and poor neurological recovery.27
Endothelial dysfunction and increased inflamma-
tion occur with aging, but their consequences are
accelerated and exacerbated by diabetes. For exam-
ple, functional MRI studies in diabetic patients
have found reductions in cerebral blood flow, par-
ticularly in subcortical regions perfused by small
vessels, associated with diabetes.28,29 Endothelial
dysfunction and inflammation also increase the sus-
ceptibility of the BBB to damage, which contributes
to an increased risk of hemorrhagic transformation,
reperfusion injury, and cerebral edema following
stroke.30 Diabetic patients exhibit altered cerebral
vasoreactivity, limiting autoregulatory control of
cerebral blood flow and stunting the development
of crucial collateral blood supply, which exacerbates
stroke injury in diabetics.31 Finally, inflammatory
processes underlying diabetes counter neural
plasticity necessary for optimal stroke recovery
(Fig. 3).
Acute hyperglycemia
Hyperglycemia is present in approximately 40%
of patients with acute ischemic stroke. Many ret-
rospective studies have found compelling asso-
ciations between admission blood glucose and
infarct growth, poor outcome, and hemorrhagic
conversion.32–35 Animal models of stroke and tis-
sue culture models of ischemia similarly demon-
strate links between hyperglycemia at the time of
infarct and increased cell death, BBB dysfunction,
and impaired fibrinolysis. The presence of hyper-
glycemia during brain ischemia promotes lactic
acid production and worsens tissue acidosis. The
production of advanced glycosylation end-products
(AGE) and reactive oxygen species (ROS) also con-
tributes to BBB breakdown.36,37 Increased infarct
size and levels of inflammatory markers are also
observed in hyperglycemic Zucker obese rats sub-
jected to experimental stroke.38 Importantly, acute
hyperglycemia also impairs cerebral autoregulation,
which can be a critical compensatory mechanism
preventing the progression of ischemic penum-
bral tissues into infarcted tissue. Studies in stroke
patients have demonstrated greater infarct growth
in patients with hyperglycemia or diabetes or both
using serial MRI.39–41 Taken together, the clinical
and mechanistic studies provide a strong scien-
tific rationale for the American Heart Association/
American Stroke Association recommendations of
treating hyperglycemia to achieve blood glucose
levels in the range of 140–180 mg/dL. To understand
if further patient benefit could be derived from
more aggressive blood glucose targets, the Stroke
Hyperglycemia Insulin Network Effect (SHINE)
study was carried out from 2012 to 2018.42 SHINE
was a multicenter randomized clinical trial of 1151

4 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal Diabetes and stroke

Figure 3. Mechanisms of stroke risk and poor stroke outcome in diabetes. Diabetes increases stroke risk, and its underlying
pathophysiological mechanisms exacerbate stroke injury and limit neuroplasticity, leading to poor stroke outcomes. Targeting the
mechanistic underpinnings of endothelial dysfunction and inflammation in diabetic stroke patients may restore neuroresilience
mechanisms and improve outcomes following stroke for diabetic patients.

patients conducted to assess the efficacy of intensive
versus standard blood glucose control in ischemic
stroke patients with diabetes or admission hyper-
glycemia (>150 mg/dL). Patients were randomized
to either intensive (80–130 mg/dL) or standard glu-
cose targets (80–170 mg/dL). The study did not
show clinical benefit to intensive insulin treatment,
despite the intensive group achieving significantly
lower blood glucose values. This indicates that the
current clinical standard of avoiding extreme hyper-
glycemia and hypoglycemia may be adequate. It
also suggests that the underlying pathophysiolog-
ical mechanisms of diabetes may be the underly-
ing poor outcome rather than hyperglycemia itself.
Of note, recent studies investigating outcomes of
diabetic patients undergoing embolectomy have
demonstrated markedly worse outcomes related to
elevated admission blood glucose.43 However, more
definitive studies are still required as other analy-
ses suggest that outcome is independent of admis-
sion blood glucose.25,44 On the basis of these results
as well as the SHINE trial, we propose that tar-
geting underlying diabetic pathophysiological pro-
cesses, such as insulin resistance (IR), endothelial
dysfunction, and aberrant immune function, will be
more likely to yield clinical benefit than addressing
acute hyperglycemia alone.
Endothelial and microvascular dysfunction
The microvasculature is a dynamic and highly
regulated component of the cardio- and cere-
brovascular systems. Endothelial cells (ECs) and
the extracellular matrix (ECM) comprising the
microvasculature are integral to cerebral function
and nutrient homeostasis. In the brain, ECs play an
important role in the maintenance and regulation of
the cerebral vasculature. T2D mellitus and IR alter
endothelial signaling pathways, resulting in dys-
functional regulation of protective vascular signals,
such as nitric oxide (NO) and prostacyclins.27,45
ECs metabolize l-arginine via endothelial nitric
oxide synthase (eNOS) to form NO. Once NO is
produced by the cell, it rapidly exerts its biolog-
ical actions by diffusing across cell membranes.
NO induces vasodilation by regulating vascu-
lar smooth muscle through activation of soluble
guanylyl cyclase, which produces cyclic guano-
sine monophosphate. NO prevents thrombosis
through inhibition of platelet surface glycoproteins,
notably the glycoprotein IIb/IIIa complex. Thus, the

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Diabetes and stroke Krinock & Singhal

production of NO by ECs regulates vasomotor tone Diabetes-related immune dysfunction and

and acts on adjacent smooth muscle cells (SMCs) inflammation
and circulating platelets and leukocytes to discour-
Systemic and local release of proinflammatory
age adhesion and thrombus formation.
cytokines exacerbates endothelial dysfunction and
Oxidative stress (OS) is a key mediator of
also independently contributes to the pathogene-
endothelial dysfunction in diabetes and metabolic
sis of diabetes and its cardiovascular complications.
syndrome (MetS) by antagonizing NO signaling.
Hyperglycemia and excess nutrient flux, resulting in
Exposure of vascular tissues to increased glucose
OS, activate the innate immune system, including
or free fatty acid concentrations induces the pro-
Toll-like receptors (TLRs).66 TLR stimulation pro-
duction of superoxide, an ROS, from NADPH
motes the production of proinflammatory cytokines
oxidase, mitochondrial sources, and uncoupling
in tissues throughout the body. The proinflamma-
of eNOS.46,47 NADPH oxidase is a major source
tory milieu coupled with endothelial dysfunction in
of superoxide in animal models of diabetes and
diabetes exacerbates stroke risk by leading to the
human vascular grafts.48 Superoxide reacts with
formation of thrombogenic plaques. Interestingly,
NO to form peroxynitrite, which uncouples the
emerging evidence links poor cognitive outcomes
biological activity of eNOS by oxidizing tetrahy-
after stroke to immune dysregulation, suggesting
drobiopterin, a critical cofactor, leading to further
that diabetic inflammation may impair mechanisms
reductions in NO synthesis.49 The loss of the bene-
of neural repair and plasticity, and also contribute to
ficial NO signaling in ECs leads to reduced vasoreg-
neurodegeneration (discussed further below).
ulatory responses, and together with the chron-
Diabetes is associated with increased activ-
ically increased inflammatory milieu in diabetic
ity of the proinflammatory transcription factor
patients, leads to impaired vascular collateraliza-
NF-κB. Hyperglycemia leads to the formation
tion, atherosclerosis, and platelet aggregation.
of AGE and activation of the mitogen-activated
Increased mitochondrial production of ROS
protein kinase pathway, both of which exacerbate
as a result of chronic hyperglycemia is another
inflammatory signaling. The IKK/NF-κB signaling
contributor to OS and inflammation in the diabetic
pathway is an important mediator connecting
vasculature.50,51 At the cellular level, increased
inflammatory and metabolic pathways in IR.67,68
ROS is driven by hyperglycemia-induced increased
The family of NF-κB transcription factors includes
diacylglycerol, which stimulates protein kinase
a collection of dimeric proteins formed from the
C (PKC) and NADPH oxidase. Overproduction
subunits p50, p52, RalA/p65, RelB, and c-Rel.
of ROS has pathological effects in diabetes by
NF-κB is located in the cytoplasm and is associated
disrupting the normal cellular regulation of adeno-
with its inhibitor IκB, but in response to cellular
sine monophosphate kinase (AMPK), leading to
stressors or inflammatory effectors (such as inter-
reduced insulin sensitivity and decreased Akt acti-
leukin (IL)-1β, tumor necrosis factor (TNF)-α,
vation in addition to the decreasing NO signaling as
or lipopolysaccharide), IκB is phosphorylated by
discussed above.52–56 Furthermore, increased ROS
IKK kinase. After ubiquitination, IκB becomes
also leads to a decline in mitochondrial biogenesis
a substrate for the proteasome, which releases
and impaired fission/fusion, a process regulated
an NF-κB dimer that can then enter the nucleus
by peroxisomal proliferator activator receptor
and regulate its target genes. In particular, in
(PPAR)-γ coactivator-1α and nuclear respiratory
vulnerable ECs, NF-κB regulates numerous inflam-
factor-1, which are dependent on eNOS and NO
matory effector molecules to express chemokines,
bioavailability.57–60 Interestingly, the mitochondrial
cytokines, and metalloproteases. This inflamma-
shift toward fission further exacerbates mitochon-
tory microenvironment stimulates the binding of
drial dysfunction and OS leading to a positive
adhesion molecules and recruits T lymphocytes
feedback cycle on further ROS generation.61–64
and monocytes/macrophages, which promote ECM
PKC activation by ROS is also a key regulator of the
remodeling, intimal hyperplasia, foam cell trans-
proinflammatory transcription factor nuclear factor
formation, and atherosclerotic lesion formation.69
kappa B (NF-κB), which acts at many target tissues
Proliferating vascular SMCs further exacerbates
to contribute to diabetes-related complications
plaque formation and contributes to a fibrous cap
discussed further below.65

6 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal
covering the plaque. The release of macrophage
proteases in advanced plaques breaks down the
fibrous cap and leads to plaque rupture, which can
precipitate thromboses and stroke.
In addition to mediating atherogenesis, inflam-
matory signals, such as NF-κB, may also be involved
in mediating poststroke immune dysfunction and
neuronal degeneration.70–72 In the brain, activation
of NF-κB can promote survival by stimulating anti-
apoptotic proteins in the context of conditioning
stimuli.73,74 In diabetes, however, excess TLR4 acti-
vation and NF-κB signaling lead to exaggerated cen-
tral and peripheral inflammatory responses, which
exacerbates neuronal injury and poor recovery in
animal studies. TLR4 is upregulated after stroke,
and TLR4-deficient mice have smaller areas of brain
infarction and lower inflammatory response after
middle cerebral artery occlusion (MCAO).75,76 Sim-
ilarly, inhibition of TLR4 signaling in mouse models
of stroke reduces neuronal cell apoptosis, decreases
hemorrhagic transformation, and improves neuro-
logical outcomes in diabetic animals.77,78 Although
a definitive link between TLR4 or NF-κB and post-
stroke neuronal degeneration remains to be shown,
sustained glial and microglial activation resulting
from CNS inflammation is strongly associated with
neuronal degeneration in numerous neurodegen-
erative and brain injury models.79–82 Prior stud-
ies have also linked NF-κB expression to neuronal
degeneration in patients with Alzheimer’s disease
(AD). Thus, additional research focused on uncov-
ering the mechanistic links between poststroke neu-
ral degeneration and inflammation may yield widely
applicable insights.83,84
Altered immune responses in diabetic stroke
patients are also an important contributor to the
poor outcome following stroke. Even in nondi-
abetic patients, poststroke immunodepression is
observed to underly the high rates of pneumo-
nia and other infections following stroke.85 Sup-
pression of neutrophil phagocytic actions has been
posited to underly susceptibility to infections in dia-
betic patients; however, more recent investigations
point to markedly exaggerated cytokine responses
and “hyperinflammation” in diabetes.86 Diabetic
stroke patients suffer infectious consequences fol-
lowing stroke more often than nondiabetic stroke
patients,87,88 reflecting a potentiation of the diabetic
immunocompromised state following stroke. Ret-
rospective studies point to a role for β-blockers in
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Diabetes and stroke
reducing infections and mortality in stroke patients.
However, it is unclear if this protective effect holds
for diabetic stroke patients.89,90 Preclinical studies
suggest that TLR4 antagonism may reduce “hyper-
inflammatory” responses; however, whether this
can also reduce poststroke immunodepression is
unknown.86
How does the diabetic milieu impair
neuroresilience mechanisms?
Poor collateral circulation leads to larger core
infarcts and reduces reperfusion efficacy
Neurons rely almost entirely on oxidative
metabolism to sustain their homeostatic func-
tions. Owing to this energetic requirement, even
just a few minutes after blood vessel occlusion
from a stroke, millions of neuronal cells within the
ischemic core rapidly die. The tissue surround-
ing the infarcted core, known as the ischemic
penumbra (Fig. 1), can remain viable with the
restoration of normal blood flow, as happens with
EVT or thrombolytic reperfusion therapies. The
presence of prominent leptomeningeal collateral
vessels plays a key role in maintaining enough
blood flow to the ischemic penumbra following
stroke and is strongly associated with functional
outcome.91–93 Leptomeningeal collateral vessels are
anastomotic connections between the distal-most
cerebral arterioles providing redundant blood
supply to branches of the middle, anterior, and
posterior cerebral arteries. Age, hypertension,
and MetS or diabetes all impact the robustness
of cerebral collateral circulation.93 In particular,
chronic endothelial dysfunction and inflamma-
tion accompanying diabetes negatively influence
cerebrovascular reactivity, and preexisting diabetic
microvascular disease impedes vascular remod-
eling, both of which are required to compensate
for acute ischemic stroke.94 For example, diabetic
mouse models demonstrate impaired recruitment
of collaterals following MCAO compared with
nondiabetic animals, which influences the extent
of ischemic injury and behavioral outcomes.95 In
patients, poor collateral circulation reduces eligi-
bility for EVT, as poor collaterals may reduce the
salvageable penumbra at the time of presentation.96
Although it is clear that collateral status impacts
stroke infarct size and outcome, treatments
to augment blood volume and flow through
collateral circulation, such as albumin, have not
7
Diabetes and stroke
proven to be effective for stroke in clinical trials.97
This failure may be related to poor patient selection
criteria in clinical trials, as many patients with
poor collaterals or nonsalvageable penumbras are
unlikely to benefit from further volume expansion
by albumin. Further studies are needed to define
specific patients subgroups that may benefit from
collateral flow augmentation treatments.96
Reperfusion hemorrhage and cellular injury fol-
lowing the restoration of blood flow to infarcted
and ischemic tissues is a significant clinical con-
cern associated with high morbidity and mor-
tality. Patients with the poor collateral flow and
diabetes suffer much higher rates of reperfusion
hemorrhage.34,98 Poorer outcomes after EVT in dia-
betic patients despite adequate large vessel reperfu-
sion may reflect increased microvascular dysfunc-
tion and susceptibility to “no-reflow.” No-reflow
refers to the absence of brain tissue perfusion
despite adequate recanalization of the large vessel
and is thought to be mediated by constriction of
pericytes. Pericytes are smooth muscle–containing
cells located at the periphery of the microvessel
wall that perform critical functions, including the
maintenance of ECs, the BBB, and microvascu-
lar blood flow.99,100 The ischemic death of peri-
cytes during stroke leads to smooth muscle con-
traction of microvessels and impairment of tissue
perfusion.101 Hyperglycemia-induced microvascu-
lar dysfunction leads to a loss of pericytes, which
has been described in diabetic retinopathy and
AD.102,103 Interestingly, in addition to contributing
to neuronal ischemia and vascular dysfunction, per-
icyte dysfunction in diabetes may also have implica-
tions for poststroke neural degeneration, as pericyte
loss exacerbates BBB dysfunction, neuroinflamma-
tion, and tau pathology in mouse models of aging
and AD.99,105
Diabetic pathophysiology impedes
neuroplasticity and stroke recovery
Cerebral endothelial dysfunction. Diabetes
slows the patient’s stroke recovery trajectory,
exacerbates poststroke cognitive decline, and
increases the risk of poststroke dementia.104,105
Even when adjusting for stroke severity and age,
diabetes is associated with a slower and poorer
recovery of function.8,106 Interestingly, in diabetic
patients without stroke, structural and func-
tional imaging studies demonstrate an increased
8 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal
burden of preexisting cerebral microvascular
lesions, which alters imaging features of regional
connectivity.107–109 This may significantly reduce
the recovery potential of diabetic stroke patients
relative to control subjects. Supporting this hypoth-
esis, Huynh and colleagues,110 using transcranial
magnetic stimulation, found that patients with
diabetes have impaired capacity for cortical plas-
ticity after an acute stroke. Similarly, diffusion
tracer tractography has found that lacunar strokes
involving the corona radiata lead to more perma-
nent disruptions in motor tracts in patients with
diabetes.111
The underlying mechanisms by which diabetes
modulates brain regional connectivity and influ-
ences recovery from injury are the areas of active
investigation, but several candidate processes have
emerged. Studies in diverse animal models of
diabetes have shown suppressed brain plasticity
processes, including neurogenesis, oligodendroge-
nesis, synaptogenesis, and axonal sprouting.112–113
Exacerbated white matter injury, suppressed neu-
rogenesis and oligodendrogenesis, and impaired
dendritic/spine plasticity have been observed in
middle-aged nicotinamide-streptozotocin dia-
betic rats following stroke.114 Neurogenesis and
synaptic reorganization are important for func-
tional improvement after stroke.115 Neurogen-
esis in animals occurs in dense clusters around
actively dividing ECs, where vascular endothelial
growth factor (VEGF) expression is high.116 Fol-
lowing stroke, the newly activated vascular ECs
increase the release of brain-derived neurotrophic
factor (BDNF), whose induction in rodents is
both spatially and temporally associated with
recruitment of new neurons, axonal growth, and
synaptogenesis.117–120 Thus, impaired neural plas-
ticity in diabetes may stem from dysfunctional
EC function. Interestingly, HMG-CoA reductase
inhibitors (statins), which are indicated and widely
prescribed after stroke, are associated with sig-
nificant improvement in functional neurologic
recovery in mice.121 The authors find that this may
not just be due to vascular benefits of statins, but
also through the promotion of neurogenesis and
neuronal plasticity by increasing the expression of
VEGF, VEGFR2, and BDNF in the ischemic border
after stroke in mice, providing further rationale
for the benefits of statins in diabetic patients with
stroke.
Krinock & Singhal
Insulin resistance. The brain is not only glucose-
sensitive but also insulin-sensitive. Beyond the
effects of insulin in cellular metabolism and the
regulation of nutrient intake, insulin also affects
cognition and neural plasticity.122 Activation of
insulin receptor and insulin-like growth factor
(IGF) receptor signaling pathways improves recov-
ery from brain injury by activating neuronal antiox-
idant defense and engaging synaptic plasticity
mechanisms.123,124 Brain insulin resistance (BIR) in
diabetes is a critical modulator of neural metabolic
functions, restorative processes, and susceptibility
to neurodegeneration in human patients and ani-
mal models of disease.125,126 A rat model of diabetes
was found to have decreased long-term potentia-
tion (LTP) in the hippocampus, a critical process
for the formation of memories.127 Rodent models of
diabetes have decreased synaptogenesis and axonal
sprouting, which are two key mechanisms under-
lying diabetes-induced cognitive deficits.128 Ani-
mal models of disease also indicate that BIR affects
stroke outcome. IGF-1 given to mice following
MCAO results in improved recovery with improved
angiogenic and neuroplasticity markers.129 Interest-
ingly, while systemic administration of insulin to
target lower blood glucose is not beneficial to stroke
patients, intranasal insulin to overcome BIR has
been posited as a potential treatment for demen-
tia and stroke. Although no results are yet available
on human trials of intranasal insulin in poststroke
recovery, it has been shown to be safe and effective
at improving cognition in small human studies of
patients with AD.130
Inflammation. Diabetes and MetS are closely
linked with inflammation, cognitive decline, and
AD in human epidemiological studies.131–134 Inter-
estingly, markers of inflammation associated with
AD activity are also found in blood and post-
mortem brains of patients months and even over 1
year after stroke.135–137 AD-like pathology, includ-
ing amyloid (A) β deposition, has also been found
in postmortem tissues of stroke survivors with cog-
nitive impairment, suggesting a mechanistic overlap
in diabetic inflammation, poststroke dementia, and
AD.138
Inflammatory cells and cytokines stimulated by
stroke or neurodegeneration have both beneficial
and detrimental effects. Activated macrophages or
microglia help brain recovery by clearing debris
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Diabetes and stroke
and stimulating trophic factors, but in pathological
states, these cells can also lead to neural injury and
impede repair.139 The opposing proinflammatory
(M1) and inflammation-resolving (M2) functions
are reflected in the spectrum of immune cellular
phenotypes acquired by microglia/macrophages
based on the time course of injury/repair and
microenvironmental milieu. Animal studies link
diabetes to exacerbated M1 macrophage polariza-
tion and microglial responses after stroke.113,140
Exacerbated release of proinflammatory cytokines
and M1 polarization of microglia limit benefi-
cial inflammatory-resolving responses typically
observed following injury.141–144 Treatments that
promote M2 polarization after stroke result in
less neuroinflammation and improve stroke
outcome.113,140 Studies have also linked M1
microglial and macrophage polarization with
reduced neurogenesis, axonal regeneration, and
synaptic density.145 However, simply ablating M1
or enhancing M2 responses does not improve out-
come after stroke in animal models,146 and further
research is required to refine the time course and
extent of M1/M2 activation required to optimize
patient recovery. Additional studies with longer-
term follow-up are also required to directly establish
a link between specific inflammatory pathways in
diabetes and poststroke dementia. Mechanistically,
animal studies have indicated that stroke in diabetic
models leads to Aβ deposition and tau hyperphos-
phorylation; however, the relationship of this with
macrophage/microglial polarization and specific
inflammatory pathways is unknown.147,148 In an
intriguing artificial intelligence–aided review of
medical records of 56 million patients with autoim-
mune diseases, patients prescribed TNF blockers
had a markedly lower risk of developing AD.149
Further clinical trials of numerous immunomodu-
lators for stroke treatment are ongoing (see below),
and specific attention should be placed on dia-
betic populations given their known underlying
pathological inflammation.
Beyond glycemic control: treatments with
multifaceted actions are needed to harness
neuroresilience mechanisms and reverse
diabetic pathophysiology
Neuroresilience following brain injury has been
described in numerous laboratory paradigms, such
9
Diabetes and stroke Krinock & Singhal

Figure 4. Therapeutics to reverse diabetic pathophysiology and enhance neuroresilience are needed to improve stroke outcome
for diabetic patients. Diabetes worsens stroke injury and antagonizes neuroresilience pathways. In particular, by increasing proin-
flammatory immune function, cellular OS, and even contributing to amyloid (A)-β deposition, diabetes leads to poor stroke
outcomes. Targeting endothelial dysfunction and inflammation with pleotropic therapies like immunomodulators, thiazolidine-
diones (TZDs), adiponectin mimetics, or exercise can stimulate neuroresilience via increased nitric oxide (NO), vascular endothe-
lial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) signaling.

as following brain injury in animals, evolved to Targeting PPARγ to enhance insulin

withstand harsh environmental conditions, or those
exposed to prior “conditioning” stimuli.150–152 Clin-
icians also frequently observe marked variability in
the improvement of patients with similar strokes
or brain injuries. Young patients, in particular, pos-
sess a remarkable degree of capacity for recovery
following brain injuries, which has been attributed
to fewer medical comorbidities facilitating less
detrimental immune responses and vigorous
mechanisms of neural plasticity.153 Specific single
nucleotide polymorphisms have also been impli-
cated in improved outcomes following stroke or
traumatic brain injury, suggesting a genetic basis for
neuroresilience mechanisms.154,155 Despite inten-
sive research efforts, these studies have not trans-
lated into a specific therapeutic to reduce the size
of the stroke acutely or to enhance stroke recovery
and outcome. This failure reflects the complexity of
the multifaceted neural recovery response and its
heterogeneity among individual patients. Given the
clear pathophysiological consequences of diabetes
to stroke risk and recovery, targeting the pleiotropic
pathways discussed above with treatments, such
as antidiabetic agents, immunomodulators, and
even exercise, to improve outcomes in diabetic
stroke patients presents a significant opportunity in
precision medicine treatment (Fig. 4).
sensitivity reduces stroke risk
Glycemic control is critical to reducing the risk of
recurrent stroke. However, glycemic control alone
may not optimize recovery from stroke in diabetic
patients.156 Pioglitazone is an antidiabetic thiazo-
lidinedione (TZD) that promotes normoglycemia
by activating PPARγ signaling in adipocytes,
immune and endothelial cells, and other tissues.
Owing to its direct beneficial effects on metabolism
and anti-inflammatory properties, pioglitazone has
also been investigated as a potential therapeutic
agent in patients with IR. The Insulin Resistance
Intervention after Stroke (IRIS) trial was designed
to test the hypothesis that pioglitazone would
reduce the rates of stroke or myocardial infarction
in a high-risk group of insulin-resistant patients
with a history of stroke or transient ischemic attack
in the last 6 months.157–159 Pioglitazone was found
to reduce rates of stroke or myocardial infarction by
approximately one-quarter. Importantly, post-hoc
analyses revealed that in patients with prediabetes
(HbA1c 5.7–6.4%), good adherence to pioglitazone
was achieved in 44.2% and resulted in significant
risk reductions in stroke and myocardial infarction
(hazard ratio [HR] 0.57, 95% confidence interval
(CI): 0.39–0.84).160 Even more encouraging, in this
subset of prediabetic patients with good treatment

10 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal
adherence, there was a marked reduction in the
5-year risk of progression to diabetes (HR 0.18, 95%
CI: 0.10–0.33). Real-world retrospective data seem
to corroborate the beneficial effects of pioglitazone
on stroke severity or recovery as well, finding that
patients admitted for stroke experienced shorter
median hospitalizations (3 versus 7 days). In spite of
these positive results, stroke neurologists have been
reluctant to adopt TZDs for stroke prevention given
safety concerns observed in the trial, including
weight gain and bone fractures requiring hospital-
ization observed in the treatment group. However, it
is important to note that historical concerns regard-
ing side effects of weight gain and bladder cancer
have been overstated in light of post-hoc and real-
world analyses, and clinicians’ neglect of pioglita-
zone should be reconsidered.161,162 In an important
post-hoc analysis of the IRIS trial, Spence and
colleagues found only a slight increase in patients
suffering from fractures in the subgroup of predia-
betic patients with good adherence to treatment. In
this subgroup, the number needed to treat (NNT)
to prevent one stroke or myocardial infarction is 24,
and the NNT to prevent diabetes is 12. Conversely,
the number needed to harm to cause a fracture is
125.160 Interestingly, smaller clinical studies have
also found that low-dose pioglitazone (7.5 mg, one-
sixth of the dose used in the IRIS trial) is effective
in improving metabolic parameters.163,164 Thus,
additional research is warranted to understand
whether lower dose pioglitazone regimens also
reduce long-term cardiovascular risk and whether
specific patient populations with reduced risk of
TZD-induced weight gain and fracture risk could
significantly increase the utilization of pioglitazone
and improve the clinical outcomes of diabetic stroke
patients.165
Interestingly, animal studies have also impli-
cated TZDs as having a neuroprotective effect
in acute stroke. In the two preclinical trials of
pioglitazone’s acute neuroprotective effects fol-
lowing transient MCAO adhering to consensus
guidelines for experimental rigor, animals given
pioglitazone in the perireperfusion period demon-
strated a marked reduction in histological infarct
volume and improvement in short-term motor
function.166,167 Gamboa and colleagues found
that even with a longer ischemic time, if piogli-
tazone is given before reperfusion, infarct size is
limited.162 In addition to these studies, 13 other
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Diabetes and stroke
published rodent studies have examined the effects
of pioglitazone as a neuroprotective agent in
various models of MCAO or focal ischemia. A
meta-analysis (of studies before 2010) determined
a cumulative beneficial effect of pioglitazone as
well as rosiglitazone, another TZD.168 However,
despite this relatively rich clinical and preclinical
literature, a human neuroprotection trial of acutely
administered pioglitazone has not been completed.
Mechanistically, further research is required to
understand the mediators of TZD actions. A variety
of effects have been postulated, including broad
anti-inflammatory and immunomodulatory prop-
erties, such as the suppression of proinflammatory
cytokines and macrophage infiltration. TZDs also
lead to enhanced NOS expression and reduced ROS
in target tissues, promote neovascularization, and
increase adiponectin secretion by adipocytes.168
Adiponectin as a candidate for engaging
neuroresilience pathways
Another important effect of PPARγ stimula-
tion and adipogenesis is increasing circulating
adiponectin.169 Adiponectin is a hormone derived
from adipose tissue and one of the most abundant
proteins found in plasma. Its levels are usually
higher in women than in men and are down-
regulated with increasing IR. Adiponectin exerts
anti-inflammatory, antiatherogenic, and insulin-
sensitizing effects as well as promotes healthier
lipid profiles.170 Total adiponectin circulates in the
bloodstream in globular, low- (LMW), medium-
(MMW), and high-molecular-weight (HMW)
forms. The biological activity of HMW adiponectin
is higher for its insulin-sensitizing effects, but
other fractions have also been associated with anti-
inflammatory effects. Meta-analyses of prospective
cohort studies have not conclusively determined
that plasma adiponectin levels are a risk factor
for stroke.171 Low plasma adiponectin levels,
however, predict an increased risk of 5-year mor-
tality after a first-ever ischemic stroke, although
further studies are required to further understand
whether a particular form of adiponectin could
serve as an important therapeutic biomarker for
TZD treatment in stroke patients.172 Thus, given
the human correlational data and strong mechanis-
tic links to vasculo- and neuroprotective actions,
adiponectin is a promising target to effect multiple
11
Diabetes and stroke
neuroresilience-promoting benefits in diabetic
stroke patients.
Protective actions of adiponectin in stroke may
also be due to pleiotropic actions, including pro-
tection against neurotoxic insults and enhancement
of EC function. Adiponectin improves endothe-
lial function in pathological inflammatory states
by suppressing ROS, activating eNOS, and increas-
ing the bioavailability of NO at the vascular
endothelium.173–175 Adiponectin also reduces the
NF-κB activation induced by hyperglycemia and
TNF-α in ECs, which prevents atherogenesis.176
In addition, adiponectin is protective in numer-
ous models of neurotoxicity, including stroke,177,178
kainate-induced excitotoxicity,179 and Aβ toxicity
during OS in vitro and in vivo.180,181 Interest-
ingly, studies in mice have shown that the loss
of adiponectin–adiponectin receptor-1 signaling in
the brain results in poor performance on cog-
nitive tests and expression of proinflammatory
cytokines and activated microglia.182 This high-
lights an important role for diabetes and MetS in
modulating the development of neurodegenerative
conditions. A further delineation of the role of
adiponectin signaling in the brain, particularly fol-
lowing stroke and brain injury, will yield important
insights into new potential treatments.
Adiponectin peptide mimetics and receptor ago-
nists are being developed, but none has under-
gone extensive study, and further research will be
required to understand their potential uses for treat-
ing diabetes and its complications. Drugs target-
ing AMPK, a major effector of adiponectin action,
maybe another avenue to target numerous antidia-
betic pathways.183 AMPK stimulation by metformin
or other drugs has been associated with improved
outcomes in animal models of stroke by improv-
ing mitochondrial function, promoting beneficial
vascular effects, and decreasing inflammation.184
However, other drugs that stimulate AMPK more
broadly, such as the adenosine analog AICAR,
have been associated with poorer outcomes after
stroke, which may reflect cell- and time-specific
windows of therapeutic effect.185,186 Thus, further
filling in knowledge gaps in our understanding of
AMPK in the regulation of energy homeostasis,
immunity, and neural plasticity is necessary to sup-
port the use of activators of AMPK in ischemic
stroke.
12 Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Krinock & Singhal
Modulating aberrant immune responses
Inflammation after stroke can persist in the brain
for months or even years. Chronic inflammatory
responses following stroke may represent a link
between impaired immunity, poor outcomes, and
increased rates of poststroke dementia after stroke
in diabetic patients.187–190 Although our knowledge
about poststroke neuroinflammation has improved,
further clinical research is necessary to establish
a clear link between diabetes, the time course
of poststroke inflammatory processes, and neuro-
logical and neuropsychiatric outcomes. Expand-
ing our understanding of the impact of diabetes
on poststroke inflammation will open the door
for immunomodulation tailored to patient-specific
variables. Numerous clinical trials of immunomod-
ulators have been performed in stroke patients;191
unfortunately, definitive phase 3 trials testing rele-
vant neuropsychiatric outcome measures are lack-
ing. However, if targeted specifically toward patients
with aberrant immune responses, such as patients
with diabetes, and outcome measures expanded to
include depression and cognition, previously trialed
therapies may yield more promising results.
Dampening diabetes-induced activation of
innate and adaptive immunity may be an impor-
tant target to encourage improved neurorecovery.
Animal studies have noted brain atrophy and
necrosis following stroke is dependent on proin-
flammatory cytokines leading to excessive protease
activity.192,193 Interestingly, high levels of IL-1β and
glucose have been linked to poststroke fatigue,194
while the elevation of IL-6 and TNF-α, which are
downstream of NF-κB, has been linked to stroke
severity and poststroke depression.195,196 Two
FDA-approved immunomodulating medications
that reduce leukocyte infiltration into the brain,
fingolimod and anakinra, have demonstrated some
encouraging biological activity in clinical trials,
though additional trials are needed to firmly estab-
lish clinical efficacy.197–199 Additionally, fasudil,
an inhibitor of neutrophil and monocyte infiltra-
tion into the brain that improves M2 polarization,
has also shown minor functional improvement
in small clinical trials.200 Tocilizumab, a mono-
clonal antibody directed against the IL-6 receptor
FDA-approved for the treatment of cytokine
release syndrome and other immune disorders,
has demonstrated efficacy in a small number of
Krinock & Singhal
animal models of stroke201 Of note, fingolimod,
fasudil, and tocilizumab are all currently being
tested in a multicenter preclinical trial sponsored
by the NINDS. This information will be partic-
ularly valuable when considering human clinical
trials, as IL-6 and subacute inflammatory responses
mediated by leukocytes, in particular, have been
implicated in early detrimental but subacute ben-
eficial neurotrophic effects in stroke and brain
injury.191,202
Exercise enhances vascular function and
neuroplasticity poststroke
Exercise and physical activity are some of the most
powerful predictors of reduced cardiovascular risk
in diabetic patients. Long-term longitudinal data
from the Nurses’ Health Study suggest that in dia-
betics, >4 h of exercise per week reduces the
risk of stroke by almost 50%.203 Prospective and
randomized clinical studies of exercise interven-
tions have found that various regimens of exer-
cise improve glycemic control204 as well as restore
healthier endothelial and metabolic phenotypes in
diabetic patients.205,206 Importantly, emerging data
also suggest that exercise and physical activity aid
in the poststroke recovery process by promoting
both angiogenesis and neuroplasticity. In fact, there
is increasing evidence that exercise-induced neu-
roplasticity is highly dependent on angiogenesis
in experimental models of recovery after ischemic
brain injury.207
Neurogenesis is extremely limited in adult
humans if present at all.208 Thus, the ability of the
brain to adapt to injuries like stroke is through
the regeneration or growth of neuronal axons,
synapses, and dendrites.209 The poststroke func-
tional recovery phase is characterized by the
resolution of inflammation coupled with coordi-
nated neurotrophic and angiogenic processes.210
As outlined above, BDNF plays a central role in
increased poststroke neuroplasticity along with
its receptor tyrosine kinase B. BDNF coordinates
structural remodeling at synaptic, axonal, and den-
dritic levels with the participation of downstream
synaptic and endothelial targets.211 Remarkably,
human and animal studies strongly link aerobic
exercise training with amplified BDNF signaling as
well as synaptic proteins, such as growth-associated
protein-43, and angiogenic factors, such as IGF-1
and VEGF.210,212–214 Evidence suggests that
Ann. N.Y. Acad. Sci. xxxx (2021) 1–21 © 2021 New York Academy of Sciences.
Diabetes and stroke
increased serum levels of BDNF are most consis-
tently observed following aerobic exercise sessions
that last more than 30 min and at a frequency of
4 days per week,215 which is very similar to 150
min weekly recommended by clinical practice
guidelines.216 In animal models of stroke, exercise
promotes angiogenesis, synaptic plasticity, and
even neurogenesis via VEGF and BDNF signal-
ing pathways that are highly dependent on NO
signaling.217,218 Physical activity is a potent inducer
of eNOS expression in the vasculature and protects
against ischemic stroke in part by helping establish
robust cerebral collateral blood supplies.219–221
Mice deficient in eNOS also demonstrate reduced
BDNF expression and poorer functional recovery
after stroke.118 BDNF improves synaptic matu-
ration and density via regulation of synapsin I
and postsynaptic density protein-95.222,223 These
interactions also facilitate excitatory glutamate
neurotransmission which supports activity depen-
dent plasticity.224–226 eNOS also plays a prominent
role in poststroke VEGF-induced proliferation of
ECs and angiogenesis.227,228 Thus, exercise acti-
vates eNOS and BDNF pathways to counter the
endothelial dysfunction of diabetes229 and activate
neuroresilience pathways to improve stroke recov-
ery. Interestingly, the use of electrical or magnetic
brain stimulation protocols to improve plasticity
following brain injury is an area of active investi-
gation that may also take advantage of pathways
similar to exercise.230–232 Plasticity induced by
transcranial magnetic or electrical stimulation is
thought to involve mechanisms of LTP, including
activation of eNOS.233 Thus, of great interest is
ongoing research aimed at optimizing exercise reg-
imens based on individual patient characteristics as
well as enhancing its effects with adjunctive brain
stimulation.
Conclusions
Diabetes is one of the most important risk factors
for stroke. Diabetic patients suffer worse stroke
outcomes, and have a poorer prognosis for recov-
ery compared with patients without diabetes. The
highest profile and largest clinical trials of diabetes
and stroke have focused on treating hyperglycemia;
however, treating hyperglycemia with insulin alone
is simply not enough to improve outcomes in dia-
betic or insulin-resistant patients. The pathophysio-
logical processes resulting from and accompanying
13
Diabetes and stroke
diabetes, including IR, endothelial dysfunction,
and inflammation, directly counter endogenous
resilience and recovery mechanisms activated fol-
lowing stroke. A pressing need exists to intensify
translational research efforts to take advantage of
the plethora of this basic science knowledge and
understand which treatments to prioritize to limit
stroke injury and optimize recovery in diabetic
stroke patients. These efforts will require both
improving animal models of stroke and performing
rigorous multicenter preclinical trials (as is being
pursued through the NINDS Stroke Preclinical
Assessment Network initiative). Well-designed
clinical trials with relevant outcomes focusing on
patients with diabetes and IR are also needed. In
addition, for treatments that have demonstrated
promise in reducing stroke and cardiovascular risk
in diabetic patients, such as pioglitazone, efforts to
increase physician adoption and further optimize
patient response are critical. Recent advances in
the primary and secondary prevention of stroke, as
well as the acute treatment of highly morbid strokes
resulting from LVO, have improved the treatment
landscape for stroke patients. However, these
treatments have not resulted in similar gains for
diabetic patients. Thus, many important unresolved
questions remain, and we are optimistic that the
combined insights from animal models and clinical
trials will ultimately provide treatments to encour-
age neuroresilience and minimize the burden of
disability from stroke in the diabetic population.
Acknowledgments
We thank the American Heart Association
(18CDA3403044) and the Hellman Family Fund
for financial support (N.S.S.).
Author contributions
Both authors participated in conceptualizing the
review, drafting the manuscript, revising its intellec-
tual content, and approved the final version of the
submitted manuscript.
Competing interests
The authors declare no competing interests.
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