Causes and pathogenesis of metabolic syndrome

Causes of Metabolic Syndrome

The main cause of metabolic syndrome is congenital or acquired insulin resistance, i.e. insensitivity of peripheral tissues (liver, muscles, adipose tissue, etc.) to insulin. Genetic predisposition to insulin resistance is associated with mutations in many genes. At the same time, a hypothesis is put forward that insulin resistance is not the cause of metabolic syndrome, but another component of it. This conclusion was made based on a study of the prevalence of metabolic syndrome components in different ethnic groups (blacks, whites in the United States, and Mexican Americans). Analysis of the data obtained allowed us to assume the presence of another genetic factor in the etiology of metabolic syndrome. This hypothetical factor was called factor Z. It interacts with insulin-sensitive tissues, endothelium, the regulatory system of arterial pressure, lipid and lipoprotein metabolism, and causes, accordingly, the development of insulin resistance, atherosclerosis, arterial hypertension, and dyslipidemia. Hyperinsulinemia in metabolic syndrome is considered a compensatory state of the body against the background of insulin resistance.

External factors that contribute to the development of insulin resistance include large meals, a sedentary lifestyle, obesity, and socio-cultural characteristics of life. In obesity, the level of free fatty acids in the blood plasma is increased. Free fatty acids inhibit the action of insulin in muscle and liver tissues and suppress glucose-stimulated insulin secretion.

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Pathogenesis of metabolic syndrome

The main mechanism of metabolic syndrome development is the development of hypersensitivity of the hypothalamic-pituitary-adrenal system. The body's response to chronic stress (depression, anxiety, smoking, alcohol consumption) is manifested by acute activation of this axis. The synthesis of cortisol, which affects the metabolism of glucose and lipids, increases. Cortisol reduces the sensitivity of muscle and liver tissue to insulin and thereby contributes to the formation of insulin resistance. In addition to increased secretion of cortisol and ACTH, women experience increased synthesis of testosterone and androstenedione, which leads to the development of hyperandrogenism. This is also facilitated by a decrease in the level of sex hormone-binding globulin in them. In men, testosterone levels decrease due to the inhibitory effect of ACTH on gonadotropin-releasing hormone. Low testosterone levels in men and high levels in women also contribute to the development of insulin resistance. High levels of cortisol and insulin, low levels of growth hormone, and in men, testosterone contribute to excess deposition of adipose tissue, primarily in the abdominal region. This is due to the high density of receptors for steroid hormones in visceral fat adipocytes. Thus, increased activity of the hypothalamic-pituitary-adrenal system can explain the development of insulin resistance and visceral obesity, which are the fundamental signs of metabolic syndrome.

In response to insulin resistance, hyperinsulinemia develops compensatorily, which plays a key role in the development of metabolic syndrome. The level of banal and postprandial (2 hours after eating or taking 75 g of glucose) insulin in metabolic syndrome is significantly increased, and this in turn increases the severity of insulin resistance. Insulin as a hormone with anabolic and anti-inflammatory effects promotes the proliferation and migration of smooth muscle cells of the vascular wall, as well as the development of obesity. These processes lead to the development of early atherosclerosis.

The risk of developing cardiovascular diseases in metabolic syndrome increases by 2-5 times, and this is largely due to hyperinsulinemia. Insulin increases the rate of cholesterol synthesis and increases the number of receptors for LDL cholesterol on cell membranes, thereby increasing the absorption of cholesterol by cells. Along with this, the process of removing cholesterol from cells with the help of HDL is inhibited. These changes in cellular cholesterol metabolism play a major role in the development of atherosclerotic plaque.

The pathogenesis of arterial hypertension, as well as other components of the metabolic syndrome, is based on hyperinsulinemia and insulin resistance. Hyperinsulinemia leads to a chronic increase in the activity of the sympathetic nervous system and sodium retention in the renal tubules. Both of these factors cause an increase in arterial pressure. A significant role is also played by chronic stimulation of beta-adrenergic receptors, causing lipolysis mainly in visceral adipose tissue and thereby increasing the level of free fatty acids. In turn, free fatty acids aggravate insulin resistance and hyperinsulinemia.

In metabolic syndrome, carbohydrate metabolism goes through three phases: from normoglycemia, with existing insulin resistance, through the phase of impaired glucose tolerance to overt type 2 diabetes mellitus. The pathogenesis of type 2 diabetes mellitus, in addition to insulin resistance, also suggests the presence of a secretory defect of insulin. There is evidence that high lipid content in beta cells causes impaired insulin secretion. Despite the fact that the daily amount of secreted insulin can be increased, the early phase of insulin secretion is lost and postprandial glycemia increases. Insulin resistance of hepatocytes is manifested by increased nocturnal glucose production by the liver, causing morning hyperglycemia on an empty stomach.

Metabolic syndrome is characterized by the development of dyslipidemia - an increase in the level of triglycerides in the blood serum and a decrease in the level of HDL. An increase in atherogenic LDL is most often detected. Dyslipidemia is based on insulin resistance/hyperinsulinemia processes.

Hyperuricemia is considered one of the components of metabolic syndrome, since it is often combined with other components of insulin resistance syndrome. The main reason for the increase in uric acid levels in blood plasma is chronic hyperinsulinemia - one of the most important pathophysiological disorders within the metabolic syndrome.

Disturbances to the hemostasis system in metabolic syndrome are identical to those observed in diabetes mellitus, but after normalization of the state of carbohydrate metabolism they do not disappear. In addition to diabetes mellitus, hyperinsulinemia, dyslipidemia, increased levels of free fatty acids, vitamin E deficiency, etc. play a role in the development of a hypercoagulable state.