Plasmapheresis for metabolic syndrome

Metabolic syndrome of insulin resistance factor combines with the development of diabetes, hypertension and obesity. Accompanied by the accumulation of various pathological products infringing microcirculation and blood flow in the vessels of the heart, brain, kidney, eyes and peripheral arteries. Drug therapy is not always able to eliminate such complications and to the forefront apheresis therapy mainly plasmapheresis.

Keywords: Metabolicsyndrome, diabetes, circulatorydisorders, plasmapheresis.

Metabolic syndrome or insulin resistance syndrome naturally accompanied not only impaired glucose tolerance and the development of diabetes mellitus type 2, but also accompanied by dyslipidemia with visceral obesity, hypertension, and prothrombotic status [Grundy S.M., 1999]. Furthermore, the metabolic syndrome is practically an early stage of development of type 2 diabetes. It has spread from 2.5 to 3.8% of the population with a doubling of the number of patients every 10-15 years. Among those older than 70 years have diabetes occurs in 10% of cases [Galenok V.A. Juk E.A., 1995]. If at the end of XX century with diabetes in the world, there were 135 million, by 2025 this number will increase to 300 million [Davis R.M. et al., 1999; Goswami G. et al., 2014]. In Russia – about 10 million people with diabetes.

With the development of obesity is arising a chain of interdependent processes. Thus, adipocyte fatty acids contribute to the output of the chylomicron, which, in turn, increase the yield of triglycerides of adipocytes. Chylomicrons act also on endothelial cells and triglycerides in them rapidly hydrolyzed lipoprotein lipase. Developing dislipoproteinemia with accumulation of low density lipoprotein, apo B, triglycerides, non-esterified fatty acids contributes to the development of insulin resistance, and that closes the vicious circle [Sniderman A.D. et al., 1997].

In this case, at the first stage, while maintaining β-cells – is possible also overproduction of insulin to compensate insulin resistance [Belyakov N.A., Chubrieva S.Y., 2007]. There is evidence that hyperinsulinemia associated with impaired lipid metabolism, in turn, contributes both to high triglyceride levels (greater than 2.5 mmol / liter) and high density lipoproteins decrease with increasing tendency to arterial hypertension. Hyperinsulinemia is also associated with increased thickness of the arterial wall [Haffner S., 1999; Irace C. et al., 1999]. Higher levels of cholesterol and triglycerides, create also favorable conditions for the development of cholelithiasis [Niemi M. et al., 1999].

Obesity contributes to the accumulation of "nonfat" tissues lipids also, leading to its degeneration. This refers to the development of fatty liver until liver cirrhosis [Rockenfeller P. et al., 2010; Firneisz G., 2014; WangX.Y., etal., 2014; Duseja A. et al., 2015]. Free fatty acid triglyceride, along with parenchymal cells accumulate in various organs, including cardiomyocytes, hepatocytes, β-cells of the pancreas, that results in chronic dysfunction of [Weinberg J.M., 2008].

In patients with cardiovascular disease, coronary artery disease and myocardial infarction show an increased level of "1 plasminogen activator inhibitor" (PAI-1). The syndrome of insulin resistance with obesity and this figure increases because PAI-1 is formed and secreted from adipocytes, and more visceral rather than subcutaneous. Level of PAI-1 is also increased in patients with Cushing's syndrome and receiving glucocorticosteroids [Morange P.-E. et al., 1999].

Interestingly, the violation of vascular reactivity and the appearance of biochemical markers of endothelial cell activation (endothelin-1, von Willebrand factor, soluble cell adhesion molecules and endothelial cell-cell adhesion) occur very early in individuals at risk of developing diabetes type 2, even at the stage of normal tolerance glucose and absence of insulin resistance [Caballero A.E. et al., 1999].

Those with the "central" type of obesity, high levels of total cholesterol, triglycerides and very low density lipoproteins, high blood pressure risk of vascular lesions arises when "pre-diabetic" (less than 6.1 mmol/l) glucose level [Laakso M., 1999]. Thus, as in pre-diabetic phase and at diagnosis of diabetes, there is often already possible to identify the presence coronary heart disease also [Irace C. et al., 1999]. In the analysis of 5522 patients 55 years and older with diabetes revealed a clear link with the metabolic syndrome and venous thromboembolism pulmonary and deep venous vessels with a frequency of 0.30-0.40 for the 5-year observation period [Ray J.G. et al., 2007].

At a metabolic syndrome the risk and frequency of ischemic strokes increases. Thus, in such cases of patients with a metabolic syndrome about 60% while among their other neurologic patients was – about 20%. There are especially subject to ischemic strokes of the woman, suffering from a metabolic syndrome [Brola W. et al., 2015; Liu L. et al., 2015]. The same can be told and about risk of coronary heart disease, especially in the senior age group which increases twice at men and by 5 times at women, suffering metabolic syndrome [Vishram J.K., 2014].

On the other hand, at a metabolic syndrome at men the hypogonadism with sexual and erectile dysfunctions develops more often [Huntaniemi I., 2014; Corona G. et al., 2015; Wickramatilake C.M. et al., 2015].

Microcirculatory disorders in diabetes compounded higher blood viscosity due to an increase in the content of fibrinogen, fibronectin, von Willebrand factor and C-reactive protein [Solerte S.B. et al., 1985].

Currently, the prevalence of metabolic syndrome takes on the character of the epidemic, especially when it starts in childhood, which further leads to the earlier development of atherosclerosis [Belyakov N.A., Chubrieva S.Y., 2007; Wang X.Y. et al., 2014]. S.W. Ryder (2007) also reported that obesity in the United States suffer 1/3 adults, and for the last 20-30 years in the 2-3 fold increase in the number of children who are overweight. Higher risk of cardiovascular disease in diabetes mellitus type 2 is associated with the accumulation of low-density lipoprotein and triglycerides due to lower high-density lipoproteins, which are anti-atherogenic factor [Riemens S. et al., 1998].

One of the causes hyperproduction VLDL is thus as insulin resistance and reduction in lipoprotein lipase activity against the raised glucose [Erkelens D.W., 1998]. After coronary bypass operations in patients with hyperglycemia and insulin resistance observed more intense progression of atherosclerotic lesions of the coronary vessels [Korpilahti K. et al., 1998]. Studies have shown a direct relationship with the increase in the degree of insulin resistance in peripheral vascular resistance, blood pressure and reduce blood flow through the peripheral vessels [Fossum E., 1998]. Also found a significant relationship between impaired glucose tolerance and vascular dementia [Curb J.D. et al., 1999; Ghosh A. et al., 2015]. Diabetes mellitus type 2 at age 55 reduces the expected individual life span of about 5 years [Vilbergsson S. et al., 1998].

However, diabetic patients can develop severe cardiomyopathy associated more with disorders of microcirculation in the myocardium than with atheromatous narrowing of the coronary arteries. It has a non-specific functional and morphological changes including: cardiomyocyte hypertrophy, interstitial fibrosis, arteriolar thickening, decreasing capillary microaneurysms their network, disturbances of left ventricular diastolic disorders first and then systolic its function also.

The development of such diabetic cardiomyopathy appears multifactorial. Pathogenetic mechanisms include greater density and stiffness with loss of elasticity due to ventricular myocardial fibrosis, microvascular disorders, disorders of energy metabolism in the myocardium, structural abnormalities of collagen, contractile proteins and cardiac muscle sarcolemma [Goodfellow J., 1997; Avendano G.F. et al., 1999; Perrone-Filardi P. et al., 2015]. At the same time the prevalence of left ventricular diastolic dysfunction can reach 85% [Ametov AS et al, 2008].

In this syndrome found more pronounced rises in blood pressure and vascular resistance during stress than the control group. This hyperreactivity is a marker for future hypertension in normotensive yet, but hyperinsulinemic obese patients [Sung B.H. et al., 1997]. Diabetes mellitus type 2 and hypertension are often linked. At the age of 45 years, about 40% of these patients have hypertension, and in 75 years – already 60%. Hypertension, in turn, increases the risk of cardiovascular disease, retinopathy and microalbuminuria in diabetes mellitus type 2 [UK prospective diabetes study group, 1998].

It is interesting to note that 53-80% of patients with hemochromatosis develop diabetes type 2. Iron is capable of catalyzing free radical stress and free radicals and lipid peroxidation plays a certain role in the etiology of this form of diabetes. Special studies have confirmed the role of iron in the delay the development of diabetes type 2 [Salonen J. et al., 1999]. By the development of diabetes as the 1st and 2nd type, there are predisposed also patients with cystic fibrosis. Glucose production by the liver when it is more intense, as well as diabetes type 2 [Hardin DS et al., 1999].

There is a definite relationship of insulin and triglyceride levels. At patients with diabetes who are treated without insulin, triglyceride concentration in the blood rises. Insulin helps reduce triglyceride levels. Most insulin dependent diabetic patients with insulin resistant and for the compensation may be chronic hyperinsulinemia, which increases the production of triglyceride-containing lipoproteins.

These changes may reflect the balance of many operations – from the increasing number of non-esterified fatty acids (NEFA) prior to the initiation of the intrahepatic production processes very low density lipoproteins (VLDL). Removal of the last performed lipoprotein lipase whose activity increases also blood levels of insulin. However, the degradation triglycerides products are atherogenic, so increasing the intensity of such degradation in diabetic patients increases the risk of atherosclerosis [Steiner G., 1997].

Under these conditions, lipemia after a fatty meal increases the activity as hepatic lipase and cholesterol esters. These factors also contribute to the formation of small LDL particles – the major atherogenic agents [Betteridge D.J., 1997]. In recent years it has been shown that TNF-a also affects the metabolism of lipids and glucose. Adipose tissue is an important source of endogenous TNF-a out-turn and the expression of such cytokine with obesity increases, which in turn contributes to the development of insulin resistance in diabetes type 2 [Yudkin J.S., 1997; Fernandez-Real J.-M. et al., 1998]. Elevated levels of ketone bodies promotes greater intensity of lipid peroxidation and hydroxyl radicals in the vascular endothelium and in erythrocytes in diabetes type 1, which contributes to the development of vascular complications [Jain S.K., McVie R., 1999]. Obesity is followed by metabolic lesions in different tissues. In particular, the maintenance of the endotoxin (lipopolysaccharide) allocated in intestines, that starts a number of pro-inflammatory and oxidative processes, some kind of – "a metabolic endotoxemia" accrues [Boutagy N.E. et al., 2015].

Thus, the presence of both immune and metabolic changes in this form of diabetes makes reasonable use of apheresis therapy at all stages of the disease. Attempts to use drugs against hypercholesterolemia, can lead to a number of adverse complications. So, clofibrate effectively reduced content of atherogenic lipids, but in patients with diabetes increased mortality from non-cardiac diseases. In particular, a 68% increased mortality of tumor diseases [Boumendil E.F., 1998]. Moreover, the treatment with statins in patients with type 2 diabetes more significantly decreased the content of antiatherogenic HDL and increased triglycerides than patients without diabetes [Bruckert E. et al., 2007].

The fact that the diet, drug therapy, insulin allow to keep blood sugar levels, but it does not prevent its oscillation, which leads to a variety of secondary metabolic disorders mainly vascular. Thus one of the reasons of the angiopathy in diabetes is to increase platelet aggregation, which depends not only on the magnitude of the concentration of sugar in the blood, but from some other pathological products affecting platelet membrane [Mazzanti L. et al., 1997].

Prolonged hyperglycemia leads to glycation of proteins. Glycation of collagen can provoke atherogenesis by receipt of lipoproteins into the extracellular matrix, making it more susceptible to oxidative modification.The end products of the process of glycation of proteins promote migration of monocytes and macrophages expression, which is an important mechanism for development of the early stages of atherogenesis. Nonenzymatic glycation end products are some of the toxic factors that determine the development of vascular complications in diabetes. Among them are the pyraline arising from the interaction of glucose with amino groups of proteins. One of the consequences of its actions is the suppression of phagocytic activity, predisposes to infectious complications, also characteristic of diabetes [Liu B.F.. etal., 1999].

Studies in recent years show that diabetes develops "oxidative stress." Due to the reduction of antioxidant status increased production of free radicals, enzymatic disorders that largely determines the secondary organ complications of diabetes [Portero-Otin M. et al., 1999]. Even with a normal level of low density lipoprotein (LDL) may be detectable markers of oxidation, such as antibodies to oxidized LDL and LDL-containing immune complexes, which seems a predisposing factor for the development of coronary artery lesions [Orchard TJ et al., 1999].

Observed in the clinic faster progression of coronary artery disease in diabetic patients is largely determined by the higher oxidative modification of lipoproteins on the background of the intensification of lipid peroxidation. However, attempts to improve the condition of vessels using long-term administration of antioxidants (vitamin E) did not lead to the desired result [Simons L.A. et al., 1999].

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