Progress on diabetic cerebrovascular diseases

Diabetic cerebrovascular diseases are defi ned as cerebral vascular diseases induced by diabetes with sugar, fat and a series of nutrient substance metabolic disorders, resulting in intracranial large and small vessel diseases. About 20-40 patients with type 2 diabetes suff er from cerebral blood vessel diseases. Diabetic cerebrovascular diseases are the main causes of death in patients with diabetes mellitus. Th e major clinical manifestations are asymptomatic cerebral atherosclerosis, stroke, cerebral small vessel disease and acute cerebral vascular disease. Th e pathogenesis, clinical characteristics, treatment and prognosis of diabetic cerebrovascular disease are obviously diff erent from non-diabetic cerebral vascular diseases. Th is paper will focus on the diabetic cerebrovascular disease, including its latest research progress. Diabetic cerebral large vascular disease and diabetic cerebral small vessel disease will be reviewed here.


INTRODUCTION
Diabetes mellitus (DM) is a type of chronic metabolic disease, of which the level of the blood glucose is above the average.Th e pathogenesis of DM is the insulin resistance or the reduction of the insulin secretion in the impaired pancreas.In the long-term development of DM, the chronic complications in patients are very complicated, including the macrovascular diseases, microvascular diseases, the complications of the nervous system and the diabetes feet.Moreover, the mechanisms of the complications are extremely complex, which are considered to be related to the hereditary susceptibility, obesity, insulin resistance, hyperglycemia, the oxidative stress or the damaged nutrition metabolism, and the factors mentioned above inducing the complications in the DM patients mutually.Th e cerebrovascular diseases in patients with DM are the most severe complications, especially in patients with type 2 DM.Th e cerebrovascular diseases include the ischemic stroke and the hemorrhagic stroke, both of which happen in patients with macrovascular disease or microvascular disease.Th e hyperglycemia in patients with type 2 DM, caused by the insulin resistance or the reduction of the insulin secretion, can induce many risk factors to damage the blood vessel, such as the various cytokines in infl ammatory reaction, the metabolic disorders of sugar or lipid, and the changes of hemodynamics.Compared with the group of cerebrovascular diseases without DM, the pathogenesis, clinical characteristics, treatment and the prognosis are more complicated in those with DM.

Pathogenesis of cerebrovascular disease in DM patients
Th e main mechanism of the cerebrovascular diseases in patients with type 2 DM is the atherosclerosis.However, it has been reported that the atherosclerosis was an infl ammatory response in essence [1].Patients with DM experience some pathologic conditions, such as long-term high blood glucose and multi-substance metabolic disturbance, which damage the blood vessel endothelium for a long time.Th e hyperglycemia and metabolic disturbance can increase the level of oxidative stress to further impair the endothelia.In the process of the endothelium damage, many cytokines and adhesion molecules are secreted in a high level, then the infl ammatory cells (including the T lymphocytes and the mononuclear leucocytes) adhere to the endarterium and move into the vascular wall.After migration into the wall, the mononuclear leucocytes adhere to the vascular wall, then go across the endothelium layer toward the vascular wall and become macrophagocytes.Th e macrophagocytes phagocytize the low density lipoprotein cholesterol which is increased  in the patients with DM, especially in those combined with hyperlipidemia.Th en these cells become the xanthoma cells.Th e blood platelets get together and adhere to the vascular wall in the infl ammatory reaction process; at the same time, the smooth muscle cells proliferate and migrate into the endarterium.When the xanthoma cells degenerate and become necrotic cells, the lipid within the cells will be released into the vascular wall, and the extracellular lipid nuclear is formed.After the lipid nuclear increase very high and the macrophagocytes become the major cells in the wall, the infl ammatory response turns up (Figure 1).Th e serum infl ammatory factors, such as C-reactive protein (CRP), interleukin-6 and interleukin-17, play a great role in the process of the vascular damage.Th ese factors induce the plaque to become erosive and to break up, then the blood platelets are activated and the thrombus is formed [2].Afterwards, the vessels become narrow or completely occlusive in the very severe cases.Some researchers found that the incidence of cerebrovascular events was signifi cantly higher in the high CRP group than in the low CRP group.It indicates that CRP may infl uence the incidence of primary cerebrovascular event in DM patients [3].Th erefore the type 2 DM is a type of low degree chronic systematic infl ammatory disease in essence.
Th e level of other biomarkers, such as homocysteine (Hcy), matrix metalloproteinase-9 (MMP-9) and serum uric acid, also rises highly in the type 2 DM patients' serum.Moreover, these biomarkers are the risk factors of the cerebrovascular diseases in DM patients and take part in the development of the atherosclerosis.Hcy damages the blood vessel endothelium directly by the oxidative stress and endoplasmic reticulum stress [4] or indirectly by the cytokine and the immune response [5].Th e MMP-9 acts on the damaged basement membrane and accelerates the unstable plaque rupture in the vessels [6].Th us the thrombosis is formed and enters into the small vessels in the brain, resulting in the cerebral infarction attack.Th e high level of the serum uric acid is caused by the metabolic disorder of protein and the hypofunction of the microvessels, which fi lter the serum uric acid in the kidney.Th e serum uric acid that can injure the blood vessel endothelium and stimulate the secretion of the cytokines is related to the development of macrovascular diseases in type 2 DM patients [7].Above all, these biomarkers are sensitive to the vascular damage and can be used to monitor the DM patients' cerebrovascular complications at the early stage.Hyperglycemia also increases lactate production and exacerbates brain tissue acidosis by increasing the available glucose for anaerobic glucose metabolism and inhibiting mitochondrial respiration.It also causes vasogenic edema, which impairs collateral blood fl ow, increases the hyperthrombotic state, decreases cerebral blood fl ow and possibly impairs cerebral autoregulation [8].
Taken together, all these factors probably increase the incidence rate of the cerebrovascular diseases tremendously.Th e risk of cerebrovascular diseases would be further increased in the DM patients who are also with hyperlipidemia or hypertension.In particular, in the DM patients with hypertension, the rate of cerebrovascular disease is apparently higher and the cerebrovascular risk increases by 2-3 fold in type 2 DM patients with elevated systolic blood pressure [9].Because of hyperglycemia, infl ammation and accumulation of the lactate, the vascular wall is damaged and the endothelial cells become necrotic, then the thrombus forms in the brain.Th e hyperlidemia in DM patients increases the blood viscosity and changes the haemodynamics, both of which maybe accelerate the development of atherosclerosis.Meanwhile, the hypertension also induces the arteriolosclerosis and fi brinoid necrosis of the wall, and even causes the microaneurysm, which is easily ruptured.All the factors act on the vascular in brain for a long time, resulting in the stroke fi nally.

Clinical classifi cation and characteristics of cerebrovascular diseases in DM patients
Th e cerebrovascular diseases complicated in DM patients include the macrovascular disease and microvascular disease.Based on the pathogenesis and the pathology, the brain vessels complications in DM patients can be divided into the ischemic cerebrovascular disease and the hemorrhagic cerebrovascular disease.Th rough the pathogenesis mentioned above, it is known that the DM can induce the ischemic cerebrovascular disease by multiple factors, such as cerebral infarction and transient ischemic attack.Th e hemorrhagic cerebrovascular disease is mainly caused by the rupture of the brain blood vessels.Th e landmark Trial of Org 10172 in Acute Stroke Treatment (TOAST) [10] classifi ed stroke into fi ve subtypes 1) large artery atherosclerosis, 2) cardioembolism, 3) small vessel occlusion (lacunar), 4) stroke of other etiology and 5) stroke of undetermined etiology (Figure 2).Th e same study found that hyperglycemia worsened outcome in non-lacunar stroke but not in lacunar stroke [11], and cerebral infarction was by far the most common type of stroke, followed by cerebral hemorrhage and subarachnoid hemorrhage [12].Researchers indicated that the incidence rate of non-lacunar stroke was higher than the lacunar stroke [13].Th e macrovascular disease induced by DM mainly aff ects the carotid artery in which the plaque causes the ischemia (such as the transient ischemic attack) in the brain.If the plaque is erosive and migrates into the small vessels in the brain, the cerebral infarction occurs.Diabetic patients who have a stroke have signifi cantly greater carotid intima-media thickness (CIMT) than both diabetic subjects without stroke and non-diabetic patients [14].Hence the CIMT can be used to forecast the incidence rate of the cerebral ischemic stroke [15].
Th e brain vessel disease in DM patients also causes the vascular cognitive impairment.In fact, several studies have evidenced that alterations of insulin homeostasis in pre-diabetes

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and diabetes increased the risk of developing cognitive decline and dementia, including vascular dementia and Alzheimer' s disease (AD).Cognitive impairment due to diabetes mainly occurs at two main periods the fi rst 5-7 years of life when brain system is in development and the period when the brain undergoes neurodegenerative changes due to aging (older than 65 years) [16].
Th e rate of hemorrhagic cerebrovascular disease in DM patients with the hypertension is higher than those without hypertension.Both hyperglycemia and hypertension can induce the risk factors to act on the brain vessels and to make them easy to be ruptured.A study showed that among those with diabetes ≥10 years, risk of ischemic stroke is 3 times higher than those without diabetes, and it also provided an evidence that the risk of ischemic stroke increased continuously with the duration of diabetes mellitus [17].It has been well documented that diabetes is associated with an increased risk of ischemic stroke [18].Th e disability ratio and mortality ratio are very high in DM patients who complicated with the cerebrovascular diseases.Higher rates of stroke in patients with diabetes, particularly in patients younger than 65, may be associated with a higher burden of disability [19].Th e morbidity of the brain complications in DM patients rises in all ages, but younger patients (30 to 44 years old) had a signifi cantly higher risk of stroke [20].Th ere are some studies showing an increased risk of developing stroke in type 2 DM patients (1.5 to 2 fold in men and 2 to 6.5 fold in women) [21].

Treatment and prognosis of cerebrovascular diseases in DM patients
Th e treatments of the cerebrovascular diseases in DM patients are divided into three levels: 1) Th e fi rst level: to prevent the brain vessels complications by controlling the blood glycose positively when the patients are at the stage of insulin resistance or at the early stage of diabetes; to reduce the risk factors caused by the hyperglycemia, which can damage the blood vessels; 2).Th e second level: to control glucose intensively after the cerebrovascular diseases occur in DM patients.Th e blood pressure should be reduced to the normal range to avoid the vasculopathy induced stroke; 3).Th e third level: to improve the cerebral circulation, which may reduce the mortality rate after the stroke in DM patients.Th rough the three levels' approach, the health condition and the quality of life could be substantially improved apparently in DM patients.Now, many treatment modalities have been applied to prevent and to treat the cerebrovascular disease in DM patients.Th ese include a tight glycemic control, an appropriate hypertension management, and reduction of LDL-C levels, all of which have been shown to reduce the stroke risk [13].
Th e most important treatment for DM patients in the fi rst two levels is to prevent the risk factors caused by hyperglycemia.Th is treatment includes forming a good life style, smoking cessation, controlling the blood pressure and the blood lipid concentration.At the stage of impaired glucose regulation or the preliminary stage of DM, the most eff ective treatment is to reduce the blood glycose to normal level, to decrease the risk factors that may damage the vessels including the infl ammation caused by hyperglycemia.Th ese measures may help prevent the development of the blood vessel complications in DM patients.Oral hypoglycemic agents can control the concentration of sugar in blood, and one study showed that there is a close association between poor glycaemic control and increased revascularization rate in T2DM [22], and normalization of glucose was associated with a reduction in mortality by 4.6 times [23].Another important way to control the process of atherosclerosis is the antiplatelet therapy, such as the treatment with acetylsalicylic acid (ASA).However, the resistance to ASA occurs in DM patients.A study showed that ASA resistance was signifi cantly higher in men, smokers and insulin users, but signifi cantly lower in beta blocker (BB) users, angiotensin-converting enzyme inhibitor (ACEI) users.However, multivariate analysis showed that insulin usage was the single eff ective parameter on ASA resistance [24].When the oral hypoglycemic agents are non-eff ective in type 2 DM patients, insulin should be applied.At the same time, the development of the atherosclerosis in brain vessels must be monitored timely, because the insulin can induce the ASA resistance.Th ere was also one research assess the endothelial dysfunction (ED) in type 2 diabetic patients and evaluate the fl ow-mediated vasodilation (FMV) in brachial artery, they thought that estimated factors infl uencing FMV might be potential therapeutic targets for presented endothelial dysfunction in type 2 diabetic patients with coronary artery disease [25].
Hypertension is the most important single risk factor.Th is risk can be decreased with antihypertensive agents by 30-40 [26].ACEIs and angiotensin receptor blocker medications have been shown to be superior to other antihypertensive medications in the prevention of stroke; and the channel blockers have also shown signifi cant benefi t in patients with diabetes [27].A recent study showed that glucagon-like peptide-1 receptor (GLP-1R) activation agonist Ex-4 (exendin-4), a drug for the treatment of T2D (Type 2 diabetes), may also have neuroprotective eff ects.Further investigation is required of GLP-1R agonists on their neuroprotective action in DM, and their potential use as anti-stroke medication in both diabetic and non-diabetic conditions [28].Patients with cerebrovascular disease are not recommended to be treated by the combination of aspirin and clopidogrel for prevention of stroke, as there is an added risk of intracerebral hemorrhage and gastrointestinal bleeding without a reduction in ischemic stroke risk [29,30].Th e patients with ischemic stroke should be treated by thrombolytic therapy in the early phase of hyperacute cerebral infarction, and the level of blood glycose should be controlled.However, both hypo-and hyperglycemia seem to carry risks in the setting of an acute ischemic stroke as shown by a J-shaped association between serum glucose levels and functional outcome in acute ischemic stroke [31], so we should avoid the hypoglycemia as much as possible in DM patients.Th ere was a study about acute lacunar stroke indicating that the stroke outcome in patient with controlled normal blood glycose was better [32].
Ischemic stroke caused by carotid atherosclerosis and carotid artery stenosis should consider an operation of carotid endarterectomy, but the operation is limited to the patients whose carotid artery stenosis are over 70 and can be taken only with the evaluation of fewer complications caused by this surgery [33].In a recent study, the impressive results of reducing stroke risk in DM have been observed with the treatment of statin (such as atorvastatin), which is eff ective in DM patients even when the LDL-C levels are normal [13].
Because of the complicated environments in vivo, it is very diffi cult to discover the accurate mechanisms, which induce the complications in cerebral vessels in DM patients.Recent breakthrough of reprogramming somatic cells into stem cells or neurons off ers a useful in vitro tool to model disorders in central nervous system [34][35][36][37][38][39][40][41][42][43][44][45].However, it will take time to simplify and mimic the in vivo system, especially at the complicated disorder status, such as in DM.

CONCLUSIONS
We conclude that the prevention of DM complications is the best approach at the moment.Th e preventive measures include good living habits, such as smoking cessation, limiting alcohol and avoiding high-glucose and high-fat diet, is an eff ective way to prevent the stroke.It helps decrease the morbidity and mortality in stroke patients with DM and improve the patients' life quality.It is notable that these treatments can only prevent the development of the complications in the brain vessels in DM patients but cannot thoroughly rescue the brain damage.More eff ective treatments are needed to prevent the occurrence and development of the cerebrovascular disease in DM patients.

FIGURE 1 .
FIGURE 1.The pathogenesis of cerebrovascular disease in diabetes mellitus.

FIGURE 2 .
FIGURE 2. A. The classifi cation of diabetic cerebrovascular diseases.B. The classifi cation of stroke in the landmark Trial of Org 10172 in Acute Stroke Treatment (TOAST) (Adapted from Adams et al., 1993).