Decreased Insulin Sensitivity and Impaired Fibrinolytic Activity in Type 2 Diabetes Patients and Nondiabetics with Ischemic Stroke

Jotić, Aleksandra; Miličić, Tanja; Šternić, Nadežda; Kostić, Vladimir; Lalić, Katarina; Jeremić, Veljko; Mijajlović, Milija; Lukić, Ljiljana; Rajković, N.; Civcic, Milorad; Maćešić, Marija; Seferović, Jelena P.; Stanarcic, J.; Aleksić, Sandra; Lalić, Nebojša

doi:10.1155/2015/934791

Cited by 15 publications

(9 citation statements)

References 48 publications

(46 reference statements)

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“…Although TAT, tPA and APC levels were unchanged in our diabetes model, PAI-1 levels were increased, a finding consistent with others [32] . High plasma PAI-1 is an independent predictor of atherothrombotic ischemic stroke in diabetics [33] . Because PAI-1 forms a complex with tPA to inhibit the fibrinolytic activity of tPA, elevated PAI-1 levels may also be important in efficacy of stroke therapy.…”

Section: Discussionmentioning

confidence: 95%

N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes

Wang

Stokes

2018

Redox Biology

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ObjectiveWe previously demonstrated that diabetes exacerbates stroke-induced brain injury, and that this correlates with brain methylglyoxal (MG)-to-glutathione (GSH) status. Cerebral injury was reversed by N-acetylcysteine (NAC). Here we tested if the pro-thrombotic phenotype seen in the systemic circulation and brain during diabetes was associated with increased MG-glycation of proteins, and if NAC could reverse this.MethodsThe streptozotocin (STZ)-induced mouse model of type 1 diabetes was used. Thrombus formation in venules and arterioles (pial circulation) was determined by intravital videomicroscopy using the light-dye method. Circulating blood platelet-leukocyte aggregates (PLAs) were analyzed by flow cytometry 1 wk before other measurements. GSH and MG levels in platelets were measured by HPLC. MG-modified proteins, glutathione peroxidase-1 (GPx-1), and superoxide dismutase-1 (SOD1) levels were detected in platelets by western blot at 20 weeks. Proteins involved in coagulation were quantified by ELISA. NAC (2 mM) was given in drinking water for 3 weeks before the terminal experiment.ResultsThrombus development was accelerated by diabetes in a time-dependent manner. % PLAs were significantly elevated by diabetes. Plasma activated plasminogen activator inhibitor type 1 levels were progressively increased with diabetes duration, with tail bleeding time reduced by 20 wks diabetes. Diabetes lowered platelet GSH levels, GPx-1 and SOD-1 expression. This was associated with higher MG levels, and increased MG-adduct formation in platelets. NAC treatment partly or completely reversed the effects of diabetes.ConclusionCollectively, these results show that the diabetic blood and brain become progressively more susceptible to platelet activation and thrombosis. NAC, given after the establishment of diabetes, may offer protection against the risk for stroke by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.

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Section: Discussionmentioning

confidence: 95%

N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes

Wang

Stokes

2018

Redox Biology

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“…In rats with diabetes there were the higher levels of TFA and EFA in the field CA1; TFA, NFA and EFA -in the fields CA2 and CA3 than in animals without it. According to some authors, violated fibrinolytic activity in diabetes is a risk factor for stroke, and its normalization is a means of this complication prevention [6,13].…”

Section: Results Of the Research And Their Discussionmentioning

confidence: 99%

Dynamics of Proteo- and Fibrinolytic Activity in Brain Structures of Rats with Diabetes Mellitus Complicated by Carotid Ischemia-Reperfusion

Tkachuk

Povar

2018

Galician med. j.

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The imbalance in the protease-antiprotease system is an integral part of the pathogenesis of acute disorder of cerebrovascular circulation and diabetes mellitus (DM), but its manifestations in the complication of diabetes by ischemia-reperfusion of the brain have not been investigated yet.The objective of the work – is to study the dynamics of carotid ischemia-reperfusion effect on the proteo- and fibrinolytic activity in brain structures of rats with experimental DM.Rats with the four-month streptozotocin DM were modeled bilateral carotene ischemia during 20 minutes. In homogenates of brain structures, indicators of proteo- fibrinolytic activity were determined after 1 hour from the beginning of reperfusion and during the 12th day of the post-ischemic period.In the absence of DM, the proteolytic activity of all or individual indicators is increased in both periods of the post-ischemic period in the cortex of the frontal and occipital lobes, the fields of hippocampus CA2 and CA3, and during the 12th day in the field CA1. In rats with diabetes, in all brain structures, there are no changes in the lysis of azo-albumin and azo-casein in both terms of observation and lysis of collagen progressively decreases.In rats without DM in the cortex of the studied particles, fields of the hippocampus CA1 and CA2, all or separate indices of fibrinolytic activity are increased in both periods of the post-ischemic period, in the field CA3 – all indices at the 12th day. In the presence of diabetes in the cortex of both studied lobes and the field CA1, the fibrinolytic activity decreases in the late post-ischemic period, in the fields of CA2 and CA3 – during both observation periods.Conclusion. In the brain structures under investigation at both time intervals, the DM eliminates the reaction of low and high molecular weight proteins to the ischemia-reperfusion and suppresses fibrinolytic activity.

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“…The clinical significance of insulin resistance is associated with coronary artery disease and ischemic stroke [ 64 , 65 ]. Metformin, a widely prescribed antidiabetes drug, is a biguanide and represents the first line of the treatment for type II diabetes mellitus [ 66 ].…”

Section: The Role Of Metformin In the Reversal Of Insulin Resistanmentioning

confidence: 99%

mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

Kezic

Popović

Lalić

2018

Oxidative Medicine and Cellular Longevity

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mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

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Decreased Insulin Sensitivity and Impaired Fibrinolytic Activity in Type 2 Diabetes Patients and Nondiabetics with Ischemic Stroke

Cited by 15 publications

References 48 publications

N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes

N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes

Dynamics of Proteo- and Fibrinolytic Activity in Brain Structures of Rats with Diabetes Mellitus Complicated by Carotid Ischemia-Reperfusion

mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

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