Abstract

Diabetes is associated with poor recovery profiles following stroke. The pathophysiological mechanisms by which diabetes mediates neurological recovery after stroke are debatable. A recent paper published in the Clinical Science by Pintana et al. (Clinical Science (2019)133, 1367–1386) provides a possible explanation for the underlying mechanisms of poor long-term motor recovery after stroke in obesity-induced diabetes animal model. Authors report that stroke-induced neurogenesis and parvalbumin (PV)+ interneuron-mediated neuroplasticity is severely impaired due to obesity-induced type 2 diabetes (T2D). Poor long-term motor recovery after stroke in comorbid obese and diabetic mice was not associated with stroke-induced grey or white matter damage. Understanding these mechanisms is crucial to develop therapeutic strategies to improve recovery in the obesity-induced diabetic population. The strength of the present study lies in the use of a comorbid obese/diabetic animal model, which is more likely to reflect the clinical scenario. However, these findings should be understood from the context of this specific animal model and whether these findings hold true for another variant of the obesity/T2D model warrants further consideration. This is an interesting study from the perspective of understanding the stroke pathology in T2D; however, the interaction of microvascular changes (including vascular modelling, angiogenesis), oxidative stress and insulin resistance (IR) associated with T2D and poor recovery profile merit further discussions. Given the increasing burden of obesity, diabetes and/or stroke globally, understanding of mechanisms may be useful in developing cardiovascular risk management pathways in this subgroup of population who are at increased risk of poor clinical outcomes following acute stroke.

Introduction

Diabetes is a known risk factor for stroke [1–3], and a recent meta-analysis showed that approximately 20–33% of acute stroke inpatients may have comorbid diabetes [4]. Despite the improvement in post-stroke functional outcomes with the increasing uptake of intravenous thrombolysis and/or endovascular thrombectomy as standards of care in acute ischaemic stroke [5], diabetic patients are at higher risk of poorer recovery profiles after stroke [6–9]. Our understanding of how diabetes or comorbidities such as obesity and diabetes, impair stroke recovery is still limited.

Neurogenesis, synaptogenesis and angiogenesis after stroke

We have evidence from experimental stroke studies that ischaemia induces neurogenesis and synaptogenesis [10,11]. Angiogenesis accompanies neurogenesis and synaptogenesis; however, few studies have demonstrated that angiogenesis precedes neurogenesis and synaptogenesis, with genes mediating angiogenesis being up-regulated within minutes of cerebral ischaemia, causing the formation of new cerebral vessels potentially causing migration of neuroblasts along new blood vessels and remodelling of axons. For favourable recovery following cerebral ischaemia, angiogenesis contributes to neuroplasticity by the remodelling of perilesional areas alongside increased axonal density from the contralesional hemisphere. Therefore, angiogenesis is increasingly being recognised as an important mechanism leading to good functional recovery after stroke [12]. Much of the focus in experimental studies has been on ipsilateral angiogenesis around infarct rather than angiogenesis on the contralesional hemisphere, except few recent studies exploring the latter; and this may have contributed to the role of angiogenesis in stroke recovery being under-appreciated.

Functional recovery in diabetic stroke

Hyperglycaemia has been reported to be independently associated with worse outcomes in a number of clinical trials [13–15]. In-hospital hyperglycaemia during the first 24 h after a stroke is linked to worse outcomes [6,16]. Implementation of evidence-based medical therapies is crucial in the management of hyperglycaemia and/or diabetes. American Stroke Association guidelines recommend treating persistent in-hospital hyperglycaemia during the first 24 h after stroke to achieve blood glucose levels in a range of 140–180 mg/dl (Class IIa; level of Evidence C).

A recent article by Pintana et al. [17] in Clinical Science sheds new light on mechanisms underlying poor motor recovery in obesity-induced diabetes. The present study is interesting from the standpoint of understanding the pathogenesis of stroke-induced damage in diabetes. Using an obesity induced-diabetes mice model, authors showed that stroke-induced hippocampal neurogenesis and parvalbumin (PV)+ interneuron-mediated neuroplasticity are severely impaired in diabetic mice vs non-diabetic mice [17]. Although this study is important from the perspective of understanding underlying cellular mechanisms, effects of diabetes on vascular remodelling after stroke, especially microvascular and macrovascular changes after stroke also need further consideration to inform clinically relevant stroke recovery profiles.

Reparative angiogenesis plays an important role in improving functional recovery following stroke [10,18,19]. However, in diabetic animals neovascularisation is impaired and angiogenesis develops clandestinely in the brain vasculature. In the event of a cerebral ischaemic event, the diabetic animals show pronounced vascular injury leading to haemorrhagic transformation, especially in areas surrounding oedema and infarct, leading to poor functional recovery profiles [18]. Prakash et al. [20] studied the vascularisation pattern after ischaemic stroke in control vs diabetic rats. Authors reported significant vasoregression in diabetic animals and that it was associated with swelling of astrocytes and poor functional outcomes in the recovery phase. Other studies also found impaired angiogenesis due to poor maturation of vessels indicated by the reduction in diameter, arteriolar density and smooth muscle cells (SMCs) despite the increase in ipsilateral vessel density 14 days after stroke [12,21–23].

Potential role of oxidative stress

Oxidative stress is implicated in the pathogenesis of diabetes and/or diabetes-induced cardiovascular disease such as ischaemic stroke [24,25]. Oxidative stress is hypothesised as a mechanism mediating macrovascular and microvascular complications in diabetic patients supported by the evidence around proven association between atherosclerosis and lipid peroxidation in plasma and within the vascular wall [25,26]. Previous studies have shown that the markers of lipid peroxidation such as thiobarbituric acid-reactive substances and lipid hydroperoxides are elevated in the plasma of diabetics [27]; thereby confirming the association between hyperglycaemia and oxidative stress [28]. Study by Kamouchi et al. [29] reported that higher levels of haemoglobin A1c (HbA1c) on admission was significantly associated with poor clinical outcomes of ischaemic stroke. The increased glucose levels in the blood can lead to the generation of reactive oxygen species (ROS) [30], free radicals and/or activation of nuclear factor NF-κB [25,26]. Moreover, the interaction of glucose with proteins in the blood leads to the formation of glycation end products; which in turn potentiates further production of ROS [31]. ROS then causes inflammatory response by initiating a chain reaction; which eventually leads to atherogenesis in the blood vessels and brain [30]. The NF-κB also mediates a number of proinflammatory and proatherosclerotic genes in vascular smooth muscle cells, endothelial cells and macrophages [32,33]. Following ischaemia/reperfusion injury, hyperglycaemia causes increase in the activity of oxidative stress and matrix metalloproteinase-9 (MMP-9). The activation of oxidative stress and MMP-9 are also implicated in blood–brain barrier (BBB) dysfunction [32]. Animal studies have postulated that excess production of superoxides may be a causal link among hyperglycaemia, MMP-9 activation and BBB dysfunction [32]. It is also suggested that obesity-induced hyperinsulinaemia, hyperglycaemia and hyperlipidaemia lead to insulin resistance (IR) [34,35], mediated by oxidative stress and inflammation [34,35]. IR has been associated with increased risk of cardiovascular diseases such as stroke, coronary artery blockage and heart failure [35].

Conclusions

Diabetes is associated with poor clinical outcomes after stroke including neurological deterioration, increased risk of haemorrhagic transformation, infarct growth, mortality and poor recovery in the rehabilitation phase. The article by Pintana et al. [17] provides new insights on the potential link between reduced neurogenesis and impaired neuroplasticity with poor motor recovery following stroke in the obesity-induced diabetes. The underlying mechanisms and pathophysiology of diabetic stroke is illustrated in Figure 1. Future experimental studies on animal models with comorbid conditions such as diabetes and obesity may provide fresh insights on how diabetes mediate stroke recovery similar to a real-world case-mix. Therapeutic approaches targeting underlying, rather interdependent, mechanisms vis-a-vis impaired angiogenesis, synaptogenesis and/or neurogenesis as well as oxidative stress and associated IR in diabetic stroke could hold promise [2,8,28,30,36,37].

Pathophysiological mechanisms mediating poor functional recovery in diabetic stroke

Author Contribution

Author contributed to the writing and overall concept of this manuscript.

Competing Interests

The author declares that there are no competing interests associated with the manuscript.

Funding

Funding from the New South Wales (NSW) Ministry of Health towards the flagship NSW Brain Clot Bank initiative is duely acknowledged [grant number 2019-2023].

Abbreviations

     
  • AGEs

    advanced glycation end products

  •  
  • BBB

    blood–brain barrier

  •  
  • IR

    insulin resistance

  •  
  • MMP-9

    matrix metalloproteinase-9

  •  
  • NF-κB

    nuclear factor kappa-light-chain-enhancer of activated B cells

  •  
  • ROS

    reactive oxygen species

  •  
  • SMC

    smooth muscle cell

  •  
  • T2D

    type 2 diabetes

References

References
1.
Hill
M.D.
(
2014
)
Stroke and diabetes mellitus.
.
Handb. Clin. Neurol.
126
,
167
174
2.
Lees
K.R.
and
Walters
M.R.
(
2005
)
Acute stroke and diabetes
.
Cerebrovasc. Dis.
20
,
9
14
[PubMed]
3.
Selvin
E.
,
Coresh
J.
,
Shahar
E.
,
Zhang
L.
,
Steffes
M.
and
Sharrett
A.R.
(
2005
)
Glycaemia (haemoglobin A1c) and incident ischaemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study
.
Lancet Neurol.
4
,
821
826
4.
Lau
L.H.
,
Lew
J.
,
Borschmann
K.
,
Thijs
V.
and
Ekinci
E.I.
(
2019
)
Prevalence of diabetes and its effects on stroke outcomes: a meta-analysis and literature review
.
J. Diabetes Invest.
10
,
780
792
5.
Bhaskar
S.
,
Stanwell
P.
,
Cordato
D.
,
Attia
J.
and
Levi
C.
(
2018
)
Reperfusion therapy in acute ischemic stroke: dawn of a new era?
BMC Neurol.
18
,
8
[PubMed]
6.
Baird
T.A.
,
Parsons
M.W.
,
Barber
P.A.
,
Butcher
K.S.
,
Desmond
P.M.
,
Tress
B.M.
et al. .
(
2002
)
The influence of diabetes mellitus and hyperglycaemia on stroke incidence and outcome
.
J. Clin. Neurosci.
9
,
618
626
7.
Li
H.W.
,
Yang
M.C.
and
Chung
K.P.
(
2011
)
Predictors for readmission of acute ischemic stroke in Taiwan
.
J. Formos. Med. Assoc.
110
,
627
633
[PubMed]
8.
Megherbi
S.E.
,
Milan
C.
,
Minier
D.
,
Couvreur
G.
,
Osseby
G.V.
,
Tilling
K.
et al. .
(
2003
)
Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from the European BIOMED Stroke Project
.
Stroke
34
,
688
694
[PubMed]
9.
Wu
S.
,
Wang
C.
,
Jia
Q.
,
Liu
G.
,
Hoff
K.
,
Wang
X.
et al. .
(
2014
)
HbA1c is associated with increased all-cause mortality in the first year after acute ischemic stroke
.
Neurol. Res.
36
,
444
452
[PubMed]
10.
Ergul
A.
,
Abdelsaid
M.
,
Abdelrahman
Y.
and
Fagan
S.C.
(
2014
)
Cerebral neovascularization in diabetes: implications for stroke recovery and beyond
.
J. Cereb. Blood Flow Metab.
34
,
553
563
11.
Zhang
L.
,
Chopp
M.
,
Zhang
Y.
,
Xiong
Y.
,
Li
C.
,
Sadry
N.
et al. .
(
2016
)
Diabetes mellitus impairs cognitive function in middle-aged rats and neurological recovery in middle-aged rats after stroke
.
Stroke
47
,
2112
2118
[PubMed]
12.
Chen
J.
,
Cui
X.
,
Zacharek
A.
,
Jiang
H.
,
Roberts
C.
,
Zhang
C.
et al. .
(
2007
)
Niaspan increases angiogenesis and improves functional recovery after stroke
.
Ann. Neurol.
62
,
49
58
[PubMed]
13.
Fang
Y.
,
Zhang
S.
,
Wu
B.
and
Liu
M.
(
2013
)
Hyperglycaemia in acute lacunar stroke: a Chinese hospital-based study
.
Diabetes Vasc. Dis. Res.
10
,
216
221
14.
Huang
J.
,
Liu
B.
,
Yang
C.
,
Chen
H.
,
Eunice
D.
and
Yuan
Z.
(
2013
)
Acute hyperglycemia worsens ischemic stroke-induced brain damage via high mobility group box-1 in rats
.
Brain Res.
1535
,
148
155
[PubMed]
15.
Zhang
Z.
,
Yan
J.
and
Shi
H.
(
2016
)
Role of hypoxia inducible factor 1 in hyperglycemia-exacerbated blood-brain barrier disruption in ischemic stroke
.
Neurobiol. Dis.
95
,
82
92
[PubMed]
16.
Allport
L.E.
,
Baird
T.A.
and
Davis
S.M.
(
2008
)
Hyperglycaemia and the ischaemic brain: continuous glucose monitoring and implications for therapy
.
Curr. Diabetes Rev.
4
,
245
257
[PubMed]
17.
Pintana
H.
,
Lietzau
G.
,
Augestad
I.L.
,
Chiazza
F.
,
Nystrom
T.
,
Patrone
C.
et al. .
(
2019
)
Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons
.
Clin. Sci. (Lond.)
133
,
1367
1386
[PubMed]
18.
Ergul
A.
,
Elgebaly
M.M.
,
Middlemore
M.L.
,
Li
W.
,
Elewa
H.
,
Switzer
J.A.
et al. .
(
2007
)
Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes
.
BMC Neurol.
7
,
33
[PubMed]
19.
Ergul
A.
,
Li
W.
,
Elgebaly
M.M.
,
Bruno
A.
and
Fagan
S.C.
(
2009
)
Hyperglycemia, diabetes and stroke: focus on the cerebrovasculature
.
Vasc. Pharmacol.
51
,
44
49
20.
Prakash
R.
,
Li
W.
,
Qu
Z.
,
Johnson
M.A.
,
Fagan
S.C.
and
Ergul
A.
(
2013
)
Vascularization pattern after ischemic stroke is different in control versus diabetic rats: relevance to stroke recovery
.
Stroke
44
,
2875
2882
[PubMed]
21.
Yan
T.
,
Venkat
P.
,
Chopp
M.
,
Zacharek
A.
,
Ning
R.
,
Cui
Y.
et al. .
(
2015
)
Neurorestorative therapy of stroke in type 2 diabetes mellitus rats treated with human umbilical cord blood cells
.
Stroke
46
,
2599
2606
[PubMed]
22.
Yan
T.
,
Ye
X.
,
Chopp
M.
,
Zacharek
A.
,
Ning
R.
,
Venkat
P.
et al. .
(
2013
)
Niaspan attenuates the adverse effects of bone marrow stromal cell treatment of stroke in type one diabetic rats
.
PLoS ONE
8
,
e81199
[PubMed]
23.
Ye
X.
,
Chopp
M.
,
Cui
X.
,
Zacharek
A.
,
Cui
Y.
,
Yan
T.
et al. .
(
2011
)
Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats
.
Exp. Neurol.
232
,
299
308
[PubMed]
24.
Xu
Y.J.
,
Tappia
P.S.
,
Neki
N.S.
and
Dhalla
N.S.
(
2014
)
Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants
.
Heart Fail. Rev.
19
,
113
121
[PubMed]
25.
Cameron
N.E.
and
Cotter
M.A.
(
1995
)
Neurovascular dysfunction in diabetic rats. Potential contribution of autoxidation and free radicals examined using transition metal chelating agents
.
J. Clin. Invest.
96
,
1159
1163
[PubMed]
26.
Wolff
S.P.
(
1993
)
Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications
.
Br. Med. Bull.
49
,
642
652
[PubMed]
27.
Kaviarasan
S.
,
Muniandy
S.
,
Qvist
R.
and
Ismail
I.S.
(
2009
)
F(2)-isoprostanes as novel biomarkers for type 2 diabetes: a review
.
J. Clin. Biochem. Nutr.
45
,
1
8
[PubMed]
28.
Chehaibi
K.
,
Trabelsi
I.
,
Mahdouani
K.
and
Slimane
M.N.
(
2016
)
Correlation of oxidative stress parameters and inflammatory markers in ischemic stroke patients
.
J. Stroke Cerebrovasc. Dis.
25
,
2585
2593
[PubMed]
29.
Kamouchi
M.
,
Matsuki
T.
,
Hata
J.
,
Kuwashiro
T.
,
Ago
T.
,
Sambongi
Y.
et al. .
(
2011
)
Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka Stroke Registry
.
Stroke
42
,
2788
2794
[PubMed]
30.
Wright
E.
Jr
,
Scism-Bacon
J.L.
and
Glass
L.C.
(
2006
)
Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia
.
Int. J. Clin. Pract.
60
,
308
314
[PubMed]
31.
Quagliaro
L.
,
Piconi
L.
,
Assaloni
R.
,
Martinelli
L.
,
Motz
E.
and
Ceriello
A.
(
2003
)
Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation
.
Diabetes
52
,
2795
2804
[PubMed]
32.
Kamada
H.
,
Yu
F.
,
Nito
C.
and
Chan
P.H.
(
2007
)
Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction
.
Stroke
38
,
1044
1049
[PubMed]
33.
Lenglet
S.
,
Montecucco
F.
and
Mach
F.
(
2015
)
Role of matrix metalloproteinases in animal models of ischemic stroke
.
Curr. Vasc. Pharmacol.
13
,
161
166
[PubMed]
34.
Ozkul
A.
,
Ayhan
M.
,
Akyol
A.
,
Turgut
E.T.
,
Kadikoylu
G.
and
Yenisey
C.
(
2013
)
The effect of insulin resistance on inflammatory response and oxidative stress in acute cerebral ischemia
.
Neuro Endocrinol. Lett.
34
,
52
57
[PubMed]
35.
Patel
T.P.
,
Rawal
K.
,
Bagchi
A.K.
,
Akolkar
G.
,
Bernardes
N.
,
Dias
D.D.S.
et al. .
(
2016
)
Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes
.
Heart Fail. Rev.
21
,
11
23
[PubMed]
36.
Ning
R.
,
Chopp
M.
,
Yan
T.
,
Zacharek
A.
,
Zhang
C.
,
Roberts
C.
et al. .
(
2012
)
Tissue plasminogen activator treatment of stroke in type-1 diabetes rats
.
Neuroscience
222
,
326
332
[PubMed]
37.
Darroudi
S.
,
Fereydouni
N.
,
Tayefi
M.
,
Ahmadnezhad
M.
,
Zamani
P.
,
Tayefi
B.
et al. .
(
2019
)
Oxidative stress and inflammation, two features associated with a high percentage body fat, and that may lead to diabetes mellitus and metabolic syndrome
.
Biofactors
45
,
35
42
[PubMed]