Effect Of Diabetes On Endothelial And Plateletts Pdf

  • and pdf
  • Sunday, May 16, 2021 2:39:29 PM
  • 5 comment
effect of diabetes on endothelial and plateletts pdf

File Name: effect of diabetes on endothelial and plateletts .zip
Size: 21791Kb
Published: 16.05.2021

Metrics details. The incidence and prevalence of diabetes mellitus is rapidly increasing worldwide at an alarming rate. Besides affecting the ability of body to use glucose, it is associated with micro-vascular and macro-vascular complications. Augmented atherosclerosis is documented to be the key factor leading to vascular complications in T2DM patients. The metabolic milieu of T2DM, including insulin resistance, hyperglycemia and release of excess free fatty acids, along with other metabolic abnormalities affects vascular wall by a series of events including endothelial dysfunction, platelet hyperactivity, oxidative stress and low-grade inflammation.

Interaction between platelets and endothelium: from pathophysiology to new therapeutic options

Diabetes mellitus DM is an extremely common disorder which carries a risk of vascular impairment. DM type 2 DM2 can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity.

These all are the reasons why DM2 is the most common acquired thrombophilia. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM. As a natural consequence of continuous investigation, many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice. Endothelial function can be assessed by the evaluation of endothelial markers, circulating molecules synthesised in various amounts by the endothelium.

These markers precede the signs of evident microangiopathy. Platelets have an ethiopathogenic relation to the microangiopathy in DM. Their increased activity was confirmed in both types of DM. Predictors of endothelial and platelet disorder could improve the screening of individuals at increased risk, thus leading to the early diagnosis, appropriate treatment, as well as to the effective prevention of the complications of DM2.

In the article we deal with the mechanisms involved in the pathogenesis of endothelial and platelet functional abnormalities, endothelial and platelet markers of DM2 considered for implementation in clinical practice and possibilities of their detection. Core tip: Number of diabetics increases, what leads to worldwide increasing diabetes-associated vascular events. Moreover, diabetes mellitus type 2 is the most common acquired thrombophilia. Therefore, to prevent life-threatening vascular complications in subjects with diabetes, mechanisms and markers of endothelial and platelet dysfunction have been investigated.

In order to contribute to better management of discussed patients and to increase knowledge about their origin, in this article we tried to summarize the pathogenesis of endothelial and platelet dysfunction and to characterize possible predictors of abnormalities of endothelium and platelets, as well as methods of their detection.

In s the attention has shifted towards haemostatic mechanisms with particular emphasis on the relationship between platelets and the vessel wall [ 1 ]. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM [ 3 ].

In fact, markers precede the signs of evident microangiopathy [ 4 ]. Microalbuminuria conventionally represents albumin excretion rate mg in a 24 h urine collection. It is associated with endothelial dysfunction and serves as a predictor of DM at levels out of the characterized reference range [ 4 , 6 ]. DM2 can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity. These all are the reasons why DM2 is the most common acquired thrombophilia [ 7 ].

Impairment of fibrinolytic system because of imbalance between regulators of plasminogen represents the typical sign of thrombophilia present in diabetes [ 7 ]. Eighty percent of individuals with DM are dying because of thrombosis [ 3 ].

The most effective tool to preserve dysfunction of the endothelium and vascular impairment in DM is the management of hyperglycaemia [ 4 ]. This review will characterize mechanisms responsible for the development of endothelial and platelet functional abnormalities, endothelial and platelet markers of DM2 considered for implementation in clinical practice and possibilities of their detection. The pathogenesis of endothelial dysfunction in both DM1 and DM2 is multifactorial [ 4 ].

The alteration of the insulin-mediated activation of nitric oxid synthase derived from endothelium is important factor of endothelial damage in the setting of DM and insulin resistance IR. On the other hand, the activation of insulin-signalling cascade is associated with the expression of endothelin-1 ET-1 , a vasoconstrictor and mitogenic substance, and proinflammatory molecules as intercellular adhesion molecule 1 ICAM-1 [ 2 ]. Reactive oxygen species and circulating markers of oxidative stress are elevated in DM, IR and obesity [ 2 ].

Systemic inflammation present in DM can impair the function of the endothelium and lead to atherosclerosis. Individuals with diabetes or obesity have elevated circulating levels of markers of inflammation, e.

Moreover, elevated levels of proinflammatory substances predict vascular complications in diabetics [ 2 ]. Activation of protein kinase C beta can be the cause of the association between inflammation, endothelial damage, and IR in DM [ 2 ].

Recent works relationship between endothelial dysfunction and impaired mitochondrial biogenesis in subjects with DM [ 2 ]. Its role in platelet adhesion is particularly important under conditions of high shear stress [ 10 ] Figure 1. For instance, Galajda et al [ 13 ] have found significant increase of vWF in DM2 subjects without vascular impairment comparing to healthy individuals 1. On the contrary, in the study of Kubisz et al [ 8 ] circulating vWF levels did not significantly increase in diabetic subgroups when comparing with the controls.

Since then, many studies have confirmed no or no independent link between vWF and DM [ 14 , 15 ]. This can be explained by the fact that the association between vWF and DM relates to the concentrations of the proinflammatory cytokine IL Thus, vWF as a product of the acute phase response is associated with the risk of DM complications, but the relation between vWF and DM is probably indirect [ 14 , 16 ].

Plasma soluble thrombomodulin TM is a marker of endothelial damage [ 8 ]. TM represents major substance of the protein C anticoagulant system [ 17 ]. It was suggested that the elevation of plasma TM concentration in patients with DM2 could be the consequence of widespread vascular damage in diabetic patients with incipient nephropathy [ 18 ].

Widespread endothelial dysfunction is present in diabetic nephropathy. Hence, plasma vWF and TM represent valuable markers of endothelial dysfunction potentially useful in early confirmation of diabetic microvascular complications [ 20 ]. Galajda et al [ 13 ] reported on the contrary to the previous studies, when comparing the DM2 patients without vasculopathy and control group, the concentrations of TM as calcium-independent marker of endothelial injury to be similar.

This is the reason to assume that only elevated concentrations of intracellular calcium Cai -depending endothelial and platelet indicators can predict the dysfunction of the endothelium [ 13 ]. Thrombin-activatable fibrinolysis inhibitor TAFI removes C-terminal lysine part from fibrin and inhibits plasminogen activation.

Taking all the facts into the consideration, TAFI represents a substantial link between coagulation and fibrinolytic processes [ 7 ]. Inverse and significant correlation of TAFI antigen and D-dimers was found in diabetic subjects supporting the function of TAFI in diabetes-induced inhibition of fibrinolytic activity [ 6 , 7 , 21 ].

It is also suggested that fibrinolysis inhibition can be mediated by TAFI in early stages of diabetes defined by microalbuminuria in DM2 subjects without macrovascular complications.

It seems that discussed process is independent from the level of plasminogen activator inhibitor-1 PAI-1 [ 6 , 8 ]. Elevated circulating levels of TAFI were present not only in individuals diagnosed DM2, but also in patients with obesity, IR and arterial hypertension [ 8 ]. On the contrary, increased total cholesterol level probably downregulates TAFI [ 6 ]. PAI-1 represents one of the most significant and quick natural inhibitors of tissue plasminogen activator tPA and urokinase-type plasminogen activator [ 7 ].

PAI-1 is produced in vascular and metabolic tissues [ 7 ]. Therefore, up-regulation of PAI-1 occurs predominantly in obese patients and presence of endothelial dysfunction [ 6 ]. PAI-1 is released to plasma predominantly from the endothelial cells [ 7 ]. This is the cause of the elevation of PAI-1 concentrations in individuals with DM2 and hypertension with endothelial dysfunction [ 6 , 22 ]. The inflammatory cytokines, as well as metabolic components are activators of PAI-1 production in the endothelial tissue [ 7 , 23 ].

Insulin has inhibiting influence on the PAI-1 synthesis in endothelial cells. Significant decrease of PAI-1 level in DM2 individuals with endothelial impairment on long-term insulin therapy was confirmed [ 7 , 24 ]. However, the mechanism of insulins action depend upon the metabolism in hepatic cells and endothelium [ 7 ]. PAI-1 overproduction belongs to the most typical signs of thrombophilia in DM2 leading to the dysfunction of fibrinolytic system [ 7 ].

It was proposed that a a decrease of PAI-1 level may be linked with a decrease in transformation to DM2. On the other hand, the finding of elevation of PAI-1 preceding DM2 thus being, in the preexistence of IR, independent of glycaemia gives unquestionable evidence that abnormality of fibrinolytic system characterized with increased PAI-1 and tPA antigen occurs nearly at the beginning of the development of metabolic disorders and is considered a risk factor for future DM and metabolic complications [ 7 ].

It may be the first consequence of increased glycosylation, and thus the deterioration of the antithrombotic potential of endothelial cells.

Moreover, the study of Morange et al [ 29 ] showed that f-TFPI has a strong correlation with endothelial markers and t-TFPI has increased relation to parameters indicating cardiovascular risk. Quick tPA release to the circulation occurs following the Cai - dependent stimulus. Therefore, the elevated total tPA is a facade masking the dysfunctional fibrinolysis in DM2 [ 6 ].

Moreover, an elevated tPA antigen concentration is a substantial feature of the IR syndrome and also relates to the inflammation. The increased tPA levels correlate with vWF and soluble TM in individuals with various locations of atherosclerotic lesions. This supports the position of tPA as an indicator of endothelial injury [ 7 ]. The tPA levels were described to be increased in DM2 in an early phase of disease while tPA levels in DM1 are increased later in presence of vascular complications.

E-selectin CD62E , expressed by endothelium, is rapidly enhanced by proinflammatory molecules [ 30 ]. At first the adhesion molecules were considered to be endothelial markers because of their general elevation in various vasculopathies [ 25 ]. It was confirmed that individuals with increased E-selectin had a significantly higher probability of the development of DM2 [ 4 ]. In particular, soluble E-selectin remained an independent marker of diabetes after exclusion of inflammation, levels of insulin and hemoglobin A1c in both men and women [ 15 , 30 ].

Increased concentrations of these cell adhesion molecules CAMs are early markers of endothelial dysfunction, cardiovascular disease and DM2 [ 30 ]. Taking everything into account, elevated concentrations of CAMs representing an increased probability of the development of diabetes highlight the link between dysfunction of the endothelium and IR [ 15 ].

Vascular endothelial growth factor VEGF is a growth factor derived from endothelial cells, stimulating their proliferation, differentiation and survival, mediating endothelium-dependent vasodilatation, inducing increased permeability in the microcirculation and participating in other supporting functions. VEGF enhances the glomerular permeability to macromolecules and leads to profound proteinuria including albuminuria. Described action has probably a role in the development of endothelial dysfunction in diabetes [ 8 ].

Highly increased plasma VEGF levels were measured in individuals with retinopathy and nephropathy when compared with the control group. Widespread endothelial dysfunction occurs at the beginning of the development of diabetic nephropathy and precedes biochemical finding of the disorder of renal functions since the significantly increased VEGF level was present already in NAU diabetics without manifestations of microvascular impairment.

VEGF ought to be evaluated only along with further markers representing the dysfunction of the endothelium, particularly soluble TM [ 8 ].

It is assumed that VEGF may be a more sensitive indicator of renal changes than microalbuminuria [ 8 , 32 ]. On the other hand, since there were no marked differences in VEGF concentrations in individuals with DM with physiological renal functions and at the beginning of the development of diabetic nephropathy, VEGF was not confirmed as a reliable marker of the progression in DM2 patients [ 8 ].

ET-1 is considered to be the most potent vasoconstrictor form of endothelin and is produced by the endothelial cells. During prolonged periods of stress caused by hyperglycaemia and IR in the course of DM2, there is a shift in the balance with more vasoconstrictors being produced compared to vasodilating agents. This leads to endothelial dysfunction and affects the permeability of the glomerular filtration barrier leading to microalbuminuria [ 33 ].

Even experimental studies suggested that ET-1 drives development of glomerulosclerosis and podocyte loss [ 34 ]. ET-1 is really significantly associated with early development of the endothelial dysfunction in the glomerulus [ 33 ]. One of the manifestations of DM is the production of subpopulation of large and hyperreactive platelets in the bone marrow.

Thrombocytopoesis is increased [ 35 , 36 ]. In obesity and DM2 increased aggregability of platelets, as well as decreased sensitivity to antiplatelet effect of insulin was confirmed [ 36 ]. Substances produced by the endothelium, represented by nitric oxide, prostacyclin and adenosine normally inhibit platelets. In diabetic patients due to the hyperglycaemia and oxidative stress the capacity of endothelium to produce prostacyclin and nitric oxide is decreased.

Thrombosis and Vascular Inflammation in Diabetes: Mechanisms and Potential Therapeutic Targets

Address correspondence to John M. Harlan, MD. Phone: ; Fax: ; E-mail: jharlan u. The authors gratefully acknowledge Dr. Rothlein, Dr. Altieri, Dr.

Diabetes mellitus DM is an extremely common disorder which carries a risk of vascular impairment. DM type 2 DM2 can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity. These all are the reasons why DM2 is the most common acquired thrombophilia. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM. As a natural consequence of continuous investigation, many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice. Endothelial function can be assessed by the evaluation of endothelial markers, circulating molecules synthesised in various amounts by the endothelium.

Cardiovascular disease remains the main cause of morbidity and mortality in patients with diabetes. The risk of vascular ischemia is increased in this population and outcome following an event is inferior compared to individuals with normal glucose metabolism. The reasons for the adverse vascular profile in diabetes are related to a combination of more extensive atherosclerotic disease coupled with an enhanced thrombotic environment. Long-term measures to halt the accelerated atherosclerotic process in diabetes have only partially addressed vascular pathology, while long-term antithrombotic management remains largely similar to individuals without diabetes. We address in this review the pathophysiological mechanisms responsible for atherosclerosis with special emphasis on diabetes-related pathways. We also cover the enhanced thrombotic milieu, characterized by increased platelet activation, raised activity of procoagulant proteins together with compromised function of the fibrinolytic system.

Diabetic concentrations of metformin inhibit platelet-mediated ovarian cancer cell progression

Javascript is currently disabled in your browser. Several features of this site will not function whilst javascript is disabled. Authors He Y , Wu N.

The reciprocal and often complex interactions with the endothelium and leucocytes are object of continuous studies and future targeted drug therapies. Low-grade inflammation, endothelial dysfunction, and platelet hyper-reactivity are all independently associated with an increased risk of cardiovascular events. In this context, antiplatelet treatment for patients with coronary artery disease CAD , beyond its major treatment impact on the reduction of thrombotic events through platelet inhibition, seems to have an important role on platelet and endothelium interplay, by decreasing inflammation, improving endothelial function and decelerating atherosclerosis progression. This review article describes the cross talk between platelets and endothelial cells ECs , in particular those who promote atherosclerosis. Moreover, we summarize the current knowledge about the influence of contemporary antiplatelet regimens with their individual characteristics on those complex processes.

Mechanisms Involved in Diabetes-Associated Platelet Hyperactivation

This open-access and indexed, peer-reviewed journal publishes review articles ideal for the busy physician. The copyright in this work belongs to Radcliffe Medical Media. Permission is required for reuse of this content. Diabetes mellitus DM , characterised by chronic hyperglycaemia, is a rapidly growing worldwide health problem.

Diabetes mellitus is a multi-factorial disease caused by a combination of genetic and environmental factors. Although insulin resistance and dysregulation of glucose and lipid homeostasis are the primary hallmarks of the disease, it is now well accepted that the morbidity and mortality associated with diabetes mostly result from micro- and macro-vascular complications [ 1 ]. An early step in the pathogenesis of the vascular complications of diabetes is the development of endothelial dysfunction which is characterised by a decrease in nitric oxide NO bioavailability, prostacyclin production and a general reduction in the anti-thrombogenic properties of vascular wall [ 2 ]. Diabetes is also characterised by an alteration of platelet function. Indeed, platelets from patients with type 1 or type 2 diabetes are hyperreactive and demonstrate increased adhesiveness as well as exaggerated aggregation and thrombus formation.

 - Кто-нибудь может мне объяснить, что это. ВАС МОЖЕТ СПАСТИ ТОЛЬКО ПРАВДА ВВЕДИТЕ КЛЮЧ______ Джабба не дождался ответа. - Похоже, кто-то очень нами недоволен, директор. Это шантаж. Больше всего похоже на требование выкупа.

 Где ключ? - потребовала. Хейл с трудом пришел в. - Ч-что произошло. - То, что ты проиграл, а больше .

5 Comments

  1. Calgiotrigro 18.05.2021 at 19:38

    A first lab in circuits and electronics yannis tsividis pdf god with us piano torwalt pdf

  2. Ferragus G. 19.05.2021 at 11:49

    God with us piano torwalt pdf briggs and stratton engine service manual pdf

  3. Melissa Y. 20.05.2021 at 22:51

    Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

  4. Robert M. 24.05.2021 at 14:28

    This article discusses the recent findings about the mechanisms involved in platelet hyperactivation in diabetes mellitus.

  5. Maggie A. 25.05.2021 at 20:45

    Mary jones cambridge international a as level biology revision guide pdf mary jones cambridge international a as level biology revision guide pdf