Type 2 diabetes mellitus without obesity pathogenesis. Mechanisms of occurrence and development of diabetes mellitus. Treatment with hypoglycemic drugs

T The term "diabetes mellitus" refers to metabolic disorders of various etiologies, characterized by the development of chronic hyperglycemia, accompanied by changes in carbohydrate, fat and protein metabolism, which is the result of a defect in the secretion and action of insulin. Diabetes mellitus leads to damage, dysfunction and development of insufficiency of various organs and systems, especially the eyes, kidneys, nerves, heart and blood vessels.

Type 2 diabetes - the most widespread form of the disease, which is characterized by impaired insulin action (insulin resistance) and insulin secretion. Type 2 diabetes can develop at any age, but more often after age 40. The onset is gradual, often against the background of overweight. Symptoms of diabetes are absent or mild. This may be due to the slow progression of the disease and, consequently, the adaptation of patients to long-term hyperglycemia. A sufficient level of C-peptide is determined, there are no autoantibodies to insulin-producing b-cells. Morphologically, at the onset of type 2 diabetes mellitus, the normal size of the pancreas is revealed, hypertrophy of b-cells may be noted. b-cells contain a large number of secretory granules. In contrast, type I diabetes mellitus is an autoimmune disease where there is an absolute deficiency of insulin as a result of destruction of b-cells.

Fig.1. The pathogenesis of type 2 diabetes

According to modern concepts, the key role in the pathogenesis of type 2 diabetes is played by violation of insulin secretion by b-cells . Signs of impaired peripheral glucose utilization are revealed. Schematically, the pathogenesis of type 2 diabetes mellitus is shown in Fig. one.

Violation of insulin synthesis can be manifested by a violation of the amino acid sequence in the insulin molecule and the conversion of proinsulin to insulin. In both cases, the produced hormone will have low biological activity, which will lead to the development of hyperglycemia. Insulin secretion can be impaired due to pathological development of b-cells with inadequate intrauterine and postnatal nutrition, with long-term glucose toxicity that maintains secretory defects in insulin secretion, and also as a result of genetic defects in the mechanism of secretion.

Peripheral insulin resistance is manifested by a violation of the absorption of glucose by peripheral tissues, primarily liver tissues, muscle and adipose tissue. The most important in its development are defects in insulin receptors (a decrease in the number and affinity or affinity for insulin) and the pathology of glucose transporters.

The number of insulin receptors is reduced in obesity, type 2 diabetes mellitus, acromegaly, Itsenko-Cushing's disease, glucocorticoid therapy, and contraceptives.

For glucose to enter the cell, a necessary condition is the normal functioning of the glucose transporter system. On fig. Figure 2 shows the transport of glucose in the adipocyte under the action of insulin. Insulin binds to the α-subunit of the receptor on the cell membrane, resulting in autophosphorylation of the β-subunit. As a result of impulse transmission inside the cell, the kinase system is activated and translocation of the glucose transporter GLUT-4 into the cell membrane occurs. This ensures the penetration of glucose into the cell. Glucose moves along the concentration gradient by diffusion, which does not require additional energy. In the kidneys, glucose uptake occurs against a concentration gradient and requires energy. Currently, 8 glucose transporters are known. The main isoforms of the family are presented in Table 1.

Rice. 2. Effect of insulin on glucose transport in the adipocyte

In recent years, enough experimental and clinical data have appeared indicating that both defects in insulin secretion and the development of peripheral insulin resistance are largely due to impaired genetic control. These data are summarized in Table 2.

The most important goals in the treatment of diabetes mellitus are: elimination of symptoms, optimal metabolic control, prevention of acute and chronic complications, achievement of the highest possible quality of life and accessibility for patients.

The most important goals in the treatment of diabetes mellitus are: elimination of symptoms, optimal metabolic control, prevention of acute and chronic complications, achievement of the highest possible quality of life and accessibility for patients.

These goals are achieved using the basic principles of treatment that are of paramount importance for patients with diabetes mellitus of both types: diabetic diet, dosed exercise, education and self-control.

If monotherapy with a diet is ineffective in type 2 diabetes, the appointment of oral sugar-lowering drugs is required. In type 1 diabetes, insulin is always prescribed.

Diet therapy for type 2 diabetes must meet the following requirements: exclusion of refined carbohydrates (sugar, honey, jam, etc.); low consumption of saturated fats, and the total fat content should not exceed 30-35% of the daily energy requirement; carbohydrates should provide 50-60%, proteins - no more than 15% of the daily caloric intake; preferential consumption of complex carbohydrates and foods rich in soluble fibers is recommended; to compile the menu, they use special tables in which all food products are divided into groups: products that can not be limited, products that need to be taken into account, and products that should be excluded; it is desirable to distribute meals evenly throughout the day; the use of calorie-free sweeteners is acceptable; if there are no contraindications, it is recommended not to limit fluid intake; limit or eliminate alcohol intake.

The issue of compensation criteria for type 2 diabetes mellitus remains very relevant. According to the recommendations of the European Diabetes Policy Group, the risk of complications is assessed as shown in Table 3.

In addition to the state of carbohydrate metabolism, it is also necessary to take into account the degree of lipid metabolism disorders and the level of blood pressure, since after hyperglycemia these factors are the main ones in the development of cardiovascular complications of diabetes mellitus.

Tableted antidiabetic drugs

Treatment of type 2 diabetes always begins with the appointment of a diet and dosed physical activity. You should also explain to the patient the need for self-monitoring and teach him how to carry it out at home using test strips (determination of glucose levels in blood and urine). In cases where this is ineffective, tablet sugar-reducing drugs are prescribed. Three groups of drugs are used: a-glucosidase inhibitors, sulfonamides and biguanides.

a-glucosidase inhibitors (acarbose) reduce the absorption of glucose in the intestine and are effective in the early stages of the disease.

More commonly used sulfonylurea derivatives , which are divided into drugs of the 1st and 2nd generation. The 1st generation drugs are less effective and are not currently used in our country. The 2nd generation drugs are active secretogens, their sugar-lowering effect is manifested at a daily dose 50-100 times less than that of the 1st generation drugs. The most used at present are gliclazide, glibenclamide, glipizide, gliquidone .

Sulfonylureas stimulate the secretion of insulin by pancreatic b-cells. Initially, the drug binds to receptors on the surface of the b-cell, closely associated with ATP-dependent K+ channels. These channels then close and the membrane depolymerizes. The opening of calcium channels after this ensures the entry of calcium ions into the b-cell and stimulation of insulin secretion. It should be borne in mind that when prescribing a number of drugs, both strengthening and weakening of the action of sulfonylurea derivatives can be noted. Drugs that reduce their effect , are: thiazide diuretics, b-blockers, corticosteroids, indomethacin, isoniazid, nicotinic acid, calcium antagonists.

Potentiate the action of these drugs : salicylates, sulfonamides, pyrazolone derivatives, clofibrate, monoamine oxidase inhibitors, anticoagulants, alcohol.

Treatment with sulfonylurea derivatives is contraindicated in Type 1 diabetes mellitus or secondary (pancreatic) diabetes mellitus, pregnancy and lactation (due to teratogenicity), surgery (major operations), severe infections, trauma, history of allergy to sulfonylureas or similar drugs, risk severe hypoglycemia.

A group of tableted sugar-lowering drugs - biguanides currently presented metformin . Unlike the above drugs, biguanides do not increase insulin secretion. The sugar-lowering effect of biguanides is manifested only if there is a sufficient amount of insulin in the blood. Biguanides enhance its effect on peripheral tissues, reducing insulin resistance. Biguanides increase glucose uptake by muscle and adipose tissue by enhancing insulin binding to receptors and increasing GLUT-4 activity. They reduce the production of glucose by the liver, the absorption of glucose in the intestine, increase its utilization, and reduce appetite. Their appointment is contraindicated in: impaired renal function, hypoxic conditions of any etiology (cardiovascular insufficiency, lung disease, anemia, infectious diseases), acute complications of diabetes mellitus, alcohol abuse, history of lactic acidosis.

insulin therapy

Patients with a long course of the disease often develop secondary resistance to oral sugar-lowering drugs. At the onset of type 2 diabetes mellitus, 2-3% of patients require insulin, and after 10-15 years from the onset of the disease, the previous treatment becomes ineffective in half of the patients and indications for insulin therapy appear. On average, 10-15% of patients with type 2 diabetes switch annually to insulin treatment.

Indications for prescribing insulin in type 2 diabetes are: a temporary increase in insulin requirements, a sharp decrease in insulin secretion, cases when hyperglycemia does not respond to other forms of therapy. Insulin therapy for type 2 diabetes can be temporary or lifelong. Temporary insulin therapy is indicated for: stress, acute illness, need for surgery, acute infections, stroke, myocardial infarction, pregnancy and lactation. Lifelong insulin therapy is prescribed for diabetes mellitus with late autoimmune onset and secondary resistance to oral sugar-lowering drugs.

Secondary resistance to tablets is a consequence of a decrease in the mass of b-cells and / or an increase in insulin resistance. Side effects of insulin therapy in type 2 diabetes are: weight gain, frequent hunger, fluid and sodium retention, risk of hypoglycemia. In this case, different regimens of insulin therapy can be used: long-acting insulin at bedtime in combination with diet therapy or daily tablet intake; twice the introduction of short-acting and prolonged-acting insulin before breakfast and dinner; combination therapy with tablets and insulin; intensive insulin therapy in basal bolus regimen for younger people.

Intensive insulin therapy involves the administration of long-acting insulin twice a day (usually before breakfast and at bedtime) and short-acting insulin before each meal. To maintain compensation for the disease at the level of normoglycemia and glucosuria, education and self-control of the patient is necessary.

To facilitate the implementation of injections, semi-automatic injectors are used - syringe pens, which use thermostable insulins. There are ready-made mixtures of insulin in which short-acting and long-acting insulins are mixed in the factory, which is convenient for patients and reduces the percentage of errors when mixing insulins by the patients themselves.

The most difficult question remains when to start insulin treatment for type 2 diabetes. It should be decided individually in each case, analyzing the indications, contraindications, goals of therapy. Achieving and maintaining stable compensation of the disease is the main condition for the prevention and timely treatment of chronic complications of diabetes mellitus.

In addition to traditional drugs, in recent years, more and more new effective drugs have been introduced into clinical practice, many of which have unique properties. Thus, new drugs are used - daily sulfonylurea derivatives - glimepiride and glipizide which can be taken once a day. A short-acting drug has also been proposed that restores insulin secretion after a meal, - repaglinide . are being studied drugs that affect peripheral insulin resistance (group of glitazones).

The development of diabetology makes it possible to ensure high metabolic control in patients with type 2 diabetes mellitus, since The doctor's arsenal includes modern tablet preparations and insulin preparations, means of their administration, self-control means, and patient education systems. All this in clinical practice makes it possible to ensure a high quality of life for the patient and delay the development of chronic complications of the disease.

I.Yu.Demidova

Type 2 diabetes mellitus is a heterogeneous disease, for the successful treatment of which a prerequisite is the impact on all links of its pathogenesis. It is now known that hereditary predisposition, lifestyle and nutrition leading to obesity, IR, impaired insulin secretion, and increased production of glucose by the liver play an important role in the pathogenesis of DM 2.

The frequency of family cases of DM 2 in different ethnic groups ranges from 30 to 50%. Concordance for DM 2 in monozygotic twins approaches 100%. The monogenic nature of the development of diabetes has been proven only for its rare forms, such as MODY-diabetes (maturity-onset diabetes of young), diabetes associated with a defect in glucokinase, diabetes with insulin resistance as a result of a defect in insulin or the a-subunit of its receptor, diabetes combined with deafness due to a defect in mitochondria, or other genetic syndromes. For "classic" DM 2, the concept of polygenic inheritance has been adopted by now.

A sedentary lifestyle and overeating lead to the development of obesity, exacerbate the existing IR and contribute to the implementation of genetic defects that are directly responsible for the development of DM 2.

Obesity, especially visceral (central, android, abdominal), plays an important role both in the pathogenesis of IR and related metabolic disorders, and DM 2. Thus, unlike subcutaneous adipose tissue cells, visceral adipocytes are characterized by reduced sensitivity to the antilipolytic action of insulin and hypersensitivity to the lipolytic action of catecholamines. This circumstance leads to the activation of lipolysis of visceral fat and the entry of a large amount of FFA into the portal circulation, and then into the systemic circulation. In contrast, subcutaneous adipose tissue is more sensitive to the inhibitory action of insulin, which promotes reesterification of FFA to TG. The IR of skeletal muscles and their predominant utilization of FFA at rest prevent the utilization of glucose by myocytes, which leads to hyperglycemia and compensatory hyperinsulinemia. In addition, FFAs prevent insulin binding to hepatocytes, which exacerbates IR at the liver level and suppresses the inhibitory effect of the hormone on hepatic gluconeogenesis (GNG). The latter circumstance causes a constant increased production of glucose by the liver. A vicious circle is formed: an increase in the concentration of FFA leads to an even greater IR at the level of adipose, muscle and liver tissue, hyperinsulinemia, activation of lipolysis and an even greater increase in the concentration of FFA.

Physical inactivity also exacerbates the existing IR. Translocation of glucose transporters GLUT-4 in muscle tissue at rest is sharply reduced. Muscle contractions during exercise increase glucose transport into myocytes by enhancing GLUT-4 translocation to the cell membrane.

Insulin resistance, which necessarily takes place in type 2 diabetes, is a condition characterized by an insufficient biological response of cells to insulin at its sufficient concentration in the blood. The IR phenomenon was described in the late 1930s. Himsworth and Kerr.

The study of genetic defects that cause the development of IR showed that in the vast majority of cases it is not associated with impaired functioning of insulin receptors. So, in a healthy person, no more than 10-15% of the cytoplasmic pool of receptors is involved for the full utilization of glucose by insulin-dependent tissues. Mutations in the insulin and insulin receptor genes are extremely rare.

On fig. Figure 1 shows the entry of glucose through the cell membrane in insulin-dependent tissues in normal and insulin resistant conditions.

Currently, IR is associated with impaired insulin action at the post-receptor (intracellular) level as a result of the following molecular defects:

- violations of the ratio of "12+" and "12-" isoforms of the insulin receptor with a predominance of low-affinity "12+" isoforms;

- an increase in the expression of Ras-like protein (Ras-like protein associated with diabetes - RAD) in muscle tissue, which positively correlated with the presence of obesity;

- mutations in the gene of the substrate of the insulin receptor SIR-1;

- excessive production of tumor necrosis factor (TNF) in adipose tissue;

- a significant decrease in the membrane concentration of specific glucose transporters GLUT-4 in muscle tissue, which was detected in patients with type 2 diabetes;

- Decreased activity of glycogen synthetase.

One of the most important consequences of IR is dyslipoproteinemia, hyperinsulinemia, AT and hyperglycemia. It has now been established that hyperglycemia plays a very important role in the disruption of insulin secretion and the development of its relative deficiency over time. The compensatory capacity of b-cells in individuals with IR is often limited due to a genetic defect in glucokinase and/or the glucose transporter GLUT-2, responsible for insulin secretion in response to glucose stimulation. On fig. 2 is a schematic representation of insulin secretion upon stimulation with glucose and arginine.

Insulin secretion in patients with type 2 diabetes is usually impaired: the 1st phase of the secretory response to an intravenous glucose load is reduced, the secretory response to mixed meals is delayed and reduced, the concentration of proinsulin and its metabolic products is increased, and the rhythm of insulin secretion fluctuations is disturbed. However, it is not entirely clear whether these changes are the result of a primary (genetic) defect in b-cells, or whether they develop secondarily due to the phenomenon of glucose toxicity, lipotoxicity (exposure to an increased concentration of FFA), or due to any other reasons. Studies of insulin secretion in individuals with mild IGT have shown that at this stage, even before an increase in fasting glycemia and with a normal level of glycated hemoglobin, the rhythm of fluctuations in insulin secretion is already disturbed. This is manifested by a decrease in the ability of /3-cells to respond with wave-like peaks of insulin secretion to wave-like fluctuations in glucose levels during the day. In addition, in response to the same glucose load, obese individuals with IR and normal glucose tolerance secrete more insulin than individuals with normal body weight and without IR. This means that in individuals with IGT, insulin secretion is already insufficient. Why does this decrease in insulin secretion occur?

It is possible that at an early stage of impaired glucose tolerance in

change in insulin secretion, the leading role is played by an increase in the concentration

FFA, which leads to the inhibition of glycolysis by inhibiting

pyruvate dehydrogenase. A decrease in the intensity of glycolysis in b-cells leads to

to a decrease in the formation of ATP, which is the most important stimulant

secretion of insulin. The role of the phenomenon of glucose toxicity in development

impaired insulin secretion in individuals with IGT is ruled out because

no hyperglycemia yet

Glucose toxicity is understood as biomolecular processes that cause the damaging effect of long-term excess glucose in the blood on insulin secretion and tissue sensitivity to insulin, which closes a vicious circle in the pathogenesis of type 2 diabetes. It follows that hyperglycemia is not only the main symptom of diabetes, but also the leading one. a factor in its progression due to the existence of the phenomenon of glucose toxicity.

With prolonged hyperglycemia, there is a weakening of insulin secretion in response to a load of glucose, while the secretory response to stimulation with arginine, on the contrary, remains enhanced for a long time. All of the listed violations of insulin secretion are eliminated while maintaining a normal level of blood glucose, which proves the important role of the phenomenon of glucose toxicity in the pathogenesis of impaired insulin secretion in type 2 diabetes.

In addition to affecting insulin secretion, glucose toxicity contributes to a decrease in the sensitivity of peripheral tissues to insulin, so the achievement and maintenance of normoglycemia will increase the sensitivity of peripheral tissues to insulin to some extent.

Thus, it is obvious that hyperglycemia is not only a marker, but also an important pathogenetic link in DM 2, which disrupts the secretion of insulin by b-cells and the utilization of glucose by tissues, which dictates the need to strive to achieve normoglycemia in patients with DM 2.

An early symptom of incipient T2DM is fasting hyperglycemia due to increased glucose production by the liver. The severity of the defect in insulin secretion at night directly correlates with the degree of fasting hyperglycemia. It is believed that IR of hepatocytes is not a primary defect, but occurs secondary under the influence of hormonal and metabolic disorders, in particular, an increase in glucagon secretion. b-cells with prolonged chronic hyperglycemia lose the ability to respond to a further increase in glycemia by reducing the production of glucagon. As a result, hepatic gluconeogenesis (GNG) and glycogenolysis increase, which is one of the reasons for the relative deficiency of insulin in the portal circulation.

An additional factor that determines the development of IR at the liver level is the inhibitory effect of FFA on the uptake and internalization of insulin by hepatocytes. Excessive influx of** FFA into the liver dramatically stimulates GNG by increasing the production of acetyl-CoA in the Krebs cycle. In addition, acetyl-CoA reduces the activity of pyruvate dehydrogenase, which leads to excessive production of lactate in the Cori cycle, one of the main substrates for GNG. In addition to the above, FFAs inhibit the activity of glycogen synthase.

Thus, summing up all of the above, the pathogenesis of DM 2 can currently be represented as the following scheme (Fig. 3).

A certain role in the pathogenesis of DM 2 in recent years is assigned to amylin and

The role of amylin in the pathogenesis of type 2 diabetes has been proven in the last 10-15 years. Amylin (islet amyloid polypeptide) is localized in secretory granules/3-cells and is normally co-secreted with insulin in a molar ratio of approximately 1:100. Its content is increased in persons with ** IR, IGT and AH. In DM 2, it is deposited as amyloid in the islets of Langerhans. Amylin is involved in the regulation of carbohydrate metabolism by modulating the rate of glucose absorption from the intestine and by inhibiting insulin secretion in response to glucose stimulation.

The role of leptin in lipid metabolism disorders and the development of type 2 diabetes has attracted close attention over the past decade. Leptin, a polypeptide synthesized by adipocytes of white adipose tissue, has an effect on the ventrolateral nuclei of the hypothalamus, regulating eating behavior. Leptin production decreases with fasting and increases with obesity (i.e., it is regulated directly by the mass of adipose tissue). A positive energy balance is accompanied by an increase in the production of insulin and leptin, which interact at the level of the hypothalamic centers, possibly through the production of the hypothalamic neuropeptide ***Y** (NP-Y).* Hunger leads to a decrease in adipose tissue mass, a decrease in insulin and leptin levels, which activates the production of the hypothalamus * NP-Y. *The latter regulates eating behavior, causing hyperphagia, weight gain, increased body fat and reduced sympathetic nervous system activity. In animals, the introduction of *NP-Y into the * ventricles of the brain causes the rapid development of obesity. Both absolute and relative leptin deficiency leads to an increase in the formation of *NP-Y* in the hypothalamus and, as a consequence, to the development of obesity. Exogenous administration of leptin in its absolute deficiency reduces the content of mRNA encoding NP-Y, in parallel with a decrease in appetite and body weight. With a relative deficiency of leptin as a result of a mutation of the gene encoding its receptor, its exogenous administration has no effect on body weight. Thus, it can be assumed that leptin deficiency (absolute or relative) leads to the loss of inhibitory control over the formation of *NP-Y*, which in turn is accompanied by neuroendocrine and autonomic disorders that play a role in the formation of the obesity syndrome.

So, the pathogenesis of DM 2 is a complex, multilevel process in which *IR plays a leading role,* impaired insulin secretion and a chronic increase in glucose production by the liver (see Fig. 2).

Therefore, when choosing therapy, it is necessary to take into account all known

today the links of the pathogenesis of this disease in order to

achieving compensation for type 2 diabetes and, thus, preventing its late complications

A new look at the pathogenesis of type II diabetes

/AT. Malyzhev, Doctor of Medical Sciences, Professor, Ukrainian Scientific and Practical Center

endocrine surgery and transplantation of endocrine organs and tissues, Kyiv /

Type II diabetes mellitus (non-insulin-dependent) is the most common form of diabetes mellitus (DM), which is clinically manifested, as a rule, in middle-aged and elderly people. The number of people suffering from this type of diabetes (up to 80% of all diabetic patients) is increasing catastrophically all over the world, taking on the character of an epidemic. About 700,000 such patients have been registered in Ukraine, and about the same number are being treated with an unidentified diagnosis for other diseases. It is predicted that the number of patients with type II diabetes in 20 years will increase to 3.5-4 million.

It is generally accepted that one of the main reasons for the development of this disease is the formation, for various reasons, of the body's resistance to insulin, which manifests itself in the formation of persistent hyperglycemia. It is believed that an increase in the level of glucose in the body underlies the occurrence of many of the complications characteristic of this form of diabetes. That is why, in the treatment of such patients, the main efforts of the endocrinologist are aimed at restoring the normal balance of glucose in the blood by stimulating the formation of insulin by pancreatic b-cells, inhibiting the absorption of carbohydrates in the intestine, increasing the sensitivity of tissues to insulin and suppressing the processes of gluconeogenesis. An opinion was formed that the development of complications of type II diabetes is directly dependent on the quality of metabolic control throughout the day. This position is also true in relation to complications that develop in type I DM - retinopathy, nephropathy, microangiopathy, neuropathy.

Complications of type II diabetes include such pathological manifestations as dyslipidemia, hypertension, hypercoagulation, obesity (in 80% of patients). Since many of these manifestations are diagnosed either simultaneously or even earlier than hyperglycemia, a natural question arises about the true causal relationship between hyperglycemia and these complications of diabetes. Firstly, they are not characteristic of insulin-dependent diabetes mellitus, and secondly, their development cannot be explained only by hyperglycemia. Of particular difficulty in determining the cause of metabolic disorders is the so-called metabolic syndrome X, which is often diagnosed in patients with type II diabetes mellitus.

The achievements of recent years in the study of the mechanisms of development of non-insulin-dependent DM have led to the formation of a fundamentally new point of view on the genesis of this disease. As a result of many studies, it has been established that for this pathology a significant increase in the level of cytokines in the blood is very characteristic: interleukin-1 (IL-1), tumor necrotic factor (TNF) and interleukin-6 (IL-6). In some cases, this phenomenon can be registered in individuals at risk, long before the clinical manifestations of DM.

These cytokines play an important role in initiating both a nonspecific immune response and in the formation of the body's general defense mechanisms. Normally, with any excessive exposure, activation of cells (mainly macrophages and dendritic cells) that produce these factors occurs. Thanks to the latter, the body activates the synthesis of acute-phase proteins and other products by the liver, stimulates the hypothalamic-pituitary-adrenal axis, increases lipolysis, increases the blood level of very low density lipoproteins (VLDL), plasminogen activator inhibitor-1 (PAI-1), a decrease in the concentration high density lipoproteins (HDL). These protective factors are short-lived. After the cessation of the harmful effects, all systems return to their normal state, and the concentration of the listed factors returns to normal. However, in individuals with a genetic predisposition to increased cytokine synthesis and with simultaneous chronic exposure to a number of factors (obesity, excessive nutrition, age, chronic stress, chronic inflammation, etc.), activation of macrophage elements can persist for a long time, which ultimately leads to the occurrence of many metabolic syndromes characteristic of type II diabetes mellitus.

Based on this point of view, the mechanisms of development of hyperglycemia in DM are considered as follows. IL-1 and TNF, as mentioned above, activate lipolysis processes in adipose tissue, which contributes to an increase in the level of free fatty acids. At the same time, fat cells produce leptin and their own TNF. These substances are blockers of the insulin signaling system, which leads to the development of insulin resistance in any body tissues. In parallel, IL-1 and TNF activate the release of contra-insular hormones, in particular, glucocorticoids and growth hormone. The latter enhance the processes of gluconeogenesis and the release of endogenous glucose into the bloodstream. In the early stages of DM development, these cytokines can stimulate the synthesis of insulin by pancreatic b-cells, thereby helping to reduce the severity of insulin resistance. In the future, the opposite may occur - IL-1 and TNF inhibit the formation of insulin, which causes suppression of glucose utilization by tissues and depression of glycogen formation.

Thus, insulin resistance, increased gluconeogenesis, and suppression of glucose utilization ultimately lead to the development of hyperglycemia and impaired glucose tolerance. It should be especially noted that the level of insulin resistance is directly related to the mass of adipose tissue, which is explained by the direct dependence of the level of TNF synthesis by the adipose cell on its volume. That is why moderate fasting of patients has a very positive effect on reducing this insulin resistance.

An increase in the level of IL-1 and TNF in the body causes the development of dyslipidemia and the development of atherosclerosis associated with it. Patients with type II diabetes mellitus are characterized by an increase in the level of VLDL, which is associated with an increase in the amount of free fatty acids as their substrate. In parallel, the concentration of HDL decreases. The cause of this phenomenon is the increased synthesis of amyloid A by the liver under the influence of cytokines. This substance replaces the aminoprotein A1 in HDL, which leads to an increase in the binding of lipoprotein by macrophages and accelerates their migration from the liver. There is an accumulation of the so-called fatty macrophages, which have a pronounced tendency to adhere to the vascular wall. An increase in the level of VLDLP contributes to their deposition on the vascular wall, especially when its structure and permeability are damaged under the influence of the same cytokines. At the same time, the vascular endothelium changes its functions, which is manifested by a decrease in the synthesis of vasodilators and an increase in the production of procoagulants and vasoconstrictors. Since IL-1 and TNF simultaneously increase the release of von Willebrand factor and PAI-1, as well as fibrinogen, a hypercoagulable state is formed with the involvement of platelets, leukocytes and monocytes to the damaged areas of the endothelium with the formation of microthrombosis. This is where the deposition of lipids and the accumulation of fatty macrophages occur. As a result, an atherosclerotic plaque is formed and atherosclerosis characteristic of these patients is clinically manifested.

Naturally, the described mechanism is very simplified, since many other factors also take part in damage to large vessels. For example, the ongoing activation of macrophages, platelets, and endothelium leads to increased secretion of various growth factors that play an important role in the pathogenesis of vascular complications of diabetes, which should be discussed separately. Macrophages contribute to the oxidation of lipids, while the latter become toxic to the vascular endothelium, which leads to their necrosis. The attraction of many cells to the vessel wall is associated with the ability of cytokines to enhance the expression of many types of adhesive molecules on the endothelium. The deposition of lipids stimulates the formation of chemotactic factors, such as IL-8, which contributes to the penetration of mononuclear cells into the depth of the vessel wall.

An increase in the level of synthesis of IL-1 and TNF also causes other manifestations of DM, in particular, hypertension. The occurrence of the latter is associated with changes in the vascular wall, which were mentioned above, as well as with an increase in the level of glucocorticoids. Steroid hormones are also responsible, apparently, for the distribution of body fat typical of these patients.

Since cytokines inhibit the formation of testosterone, patients with diabetes often experience a decrease in sexual function. It is possible that the depressive states of patients are directly related to the known effect of IL-1 on the higher parts of the nervous system.

Thus, a new point of view on the pathogenesis of non-insulin-dependent diabetes mellitus is based on the fact that inadequate levels of interleukin-1 and tumor necrotic factor play a primary role in the genesis of most pathological syndromes. It becomes clear that their formation occurs independently and does not depend directly on hyperglycemia. At the same time, the latter makes a certain contribution to the development of other manifestations of diabetes. The fact is that an increased level of glucose leads to non-enzymatic glycation of protein molecules, both circulating and embedded in the cell membrane. This can lead to disruption of intercellular interactions, disruption of cell response to specific ligands, and changes in the complementarity of substrate-enzyme complexes. Moreover, vascular endothelium and macrophages carry specific receptors for glycated proteins. When they interact, the functions of the corresponding cellular elements are activated. As a result, the synthesis of cytokines, which were discussed above, the release of endothelial growth factor, stimulation of the formation of PAI-1, etc., is enhanced. Naturally, this leads to the aggravation of already identified metabolic disorders and to the emergence of new ones. This is of particular importance in relation to the pathology of small vessels and the development of microangiopathies. Prerequisites are being created for the development of typical complications and for type I diabetes mellitus.

Based on the foregoing, we can conclude that the principles of treatment of type II diabetes mellitus should be radically revised. Obviously, the management of carbohydrate metabolism alone is symptomatic and far from sufficient. Treatment should be supplemented by the simultaneous and as early as possible the use of drugs that modulate lipid metabolism, hemostasis and the activity of the hypothalamic-pituitary-adrenal system. But the most adequate therapy for DM seems to be therapy aimed at suppressing the increased production of cytokines that cause this complex metabolic syndrome. The search for appropriate drugs and approaches is an urgent task of modern medicine.

Impact on insulin resistance - a step forward in the treatment of diabetes

type 2 diabetes

Every year, a large number of studies are conducted in the world on diabetes mellitus (DM), the study of its pathogenetic features, diagnostic issues, and the search for new effective means of controlling and preventing complications. Such close interest in this problem is caused by an increase in the number of patients with diabetes. Every 10–15 years, their number is about doubling, mainly due to the addition of type 2 diabetics. If earlier it was believed that type 2 diabetes is a disease that occurs in middle and old age, today it is increasingly diagnosed in younger people, there are cases of insulin resistance even in children. The mortality rate among patients with diabetes is significantly higher than among other categories of patients in all age groups, regardless of gender and ethnicity. The reason for this is the severe complications associated with metabolic disorders in diabetes. Atherosclerosis, arterial hypertension, myocardial infarction, stroke - a significant proportion of the causes of these pathologies belongs to diabetes.

Despite the difficulties caused by the heterogeneity of the causes of this disease, the efforts of medical scientists and pharmacologists around the world are aimed at creating a universal pathogenetic agent that would stop the growth of the incidence of diabetes and solve a number of medical and social problems.

Insulin resistance and impaired pancreatic β-cell function are the two main endocrine disorders that characterize type 2 diabetes.

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β-cell dysfunction, like insulin resistance, is determined by genetic and environmental factors. The former include the individual rate of cell division and death, neogenesis, as well as the expression of factors responsible for insulin synthesis. External causes can be infections, exocrine pathology of the pancreas, and others.

The widely acclaimed UKPDS study found that the majority of type 2 diabetic patients had β-cell function that was half normal at the time of diagnosis. The gradual deterioration of the response to normal insulin levels and the inability of pancreatic b-cells to produce enough insulin to maintain normal glycemic levels lead to the progression of the pathological process and the development of complications of diabetes.

Unlike existing oral hypoglycemic agents, a new class of drugs - glitazones directly affect the mechanisms of development of insulin resistance and contribute to the preservation of the function of b-cells. The most studied and widely used is rosiglitazone (*Avandia*). Its predecessor, troglitazone, has not found clinical use due to high hepatotoxicity. Despite belonging to the same class of chemical compounds, Avandia differs significantly from troglitazone in structure, metabolism and excretion from the body, while potentially hepatotoxic substances are not formed.

Avandia is a highly selective agonist of ligand-activated nuclear hormone receptors PPARg present in insulin target cells in adipose tissue, skeletal muscle and liver.

Binding of Avandia to PPARg selectively activates gene transcription in target cells and, as a result, affects the expression of genes such as PEPCK, GLUT, lipoprotein lipases and TNFb, which play a critical role in carbohydrate and fat metabolism.

At the molecular level, the agonism of the drug to PPARg in the presence of insulin is manifested as follows:

Accelerates the differentiation of preadipocytes into mature adipocytes and enhances the expression of adipose-specific genes (for example, PEPCK and aP2);

Enhances the expression of GLUT-4 (an insulin-dependent substance - a glucose transporter) in mature adipocytes and skeletal muscles;

Increases the translocation of GLUT-4 from intracellular vesicles to the cell membrane, thus facilitating the transport of glucose into adipocytes and skeletal muscle cells;

Counteracts the effects of TNFb by increasing adipocyte differentiation, insulin-dependent glucose transport, GLUT-4 expression, and decreasing free fatty acid release.

In general, Avandia enhances glucose deposition in skeletal muscle and adipose tissue and reduces hepatic glucose release. The drug increases the sensitivity of adipocytes to insulin and their ability to capture glucose and store lipids. This inhibits lipolysis, which in turn reduces systemic glycerol and free fatty acids (FFA). An increase in their number has a pronounced effect on glucose homeostasis, reducing its uptake, oxidation and storage in muscle tissue. FFAs also play a role in the pathogenesis of insulin resistance by reducing insulin-stimulated glucose uptake, activating hepatic gluconeogenesis, and inhibiting muscle glycogen synthesis. In addition, an increased amount of FFA significantly limits the secretion of insulin by b-cells. Thus, a decrease in FFA during treatment with Avandia increases tissue sensitivity to insulin and glycemic control.

In addition, as in adipocytes, PPARg agonists increase glucose uptake by muscle cells, which has a positive effect on glycemic levels. Avandia inhibits hepatic glucose production, which may also (at least in part) be due to reduced free fatty acids.

Due to its highly selective and potent PPARg agonism, Avandia reduces insulin resistance by restoring the ability of the liver, adipose tissue and muscle to respond to insulin, and thus provides control of glucose levels.

Preclinical data suggest that Avandia has a protective effect on pancreatic b-cell function, but it is still unclear whether the positive effect of the drug is due to its direct effect on these cells. It is assumed that the therapeutic effect is due to a decrease in glucose and fatty acid levels, as well as hyperinsulinemia, which, in general, has a preserving effect on the pancreas.

The effectiveness of Avandia has been confirmed in a large-scale clinical trial program involving five thousand patients in Europe and the United States with type 2 diabetes. In studies where Avandia was given as add-on therapy to patients who did not respond well to maximum and submaximal doses of a sulfonylurea or metformin, there was an apparent clinically significant and additive improvement in glucose control. In addition, this effect was achieved without exacerbating any of the known side effects of sulfonylurea or metformin, which are observed with monotherapy with these drugs.

As shown by the UKPDS study, in 50% of patients with type 2 diabetes, monotherapy with metformin or sulfonylurea derivatives ceases to provide adequate glycemic control for three years. Patients with type 2 diabetes mellitus for an average of 9 years were included in the Avandia clinical study program. In this regard, its effect on glycemia becomes even more important, since only patients with newly diagnosed diabetes took part in the UKPDS study, that is, the disease was at an earlier stage. In addition, the efficacy of Avandia remained constant throughout the program, in contrast to the UKPDS study.

There is reason to believe that the new drug slows the progression of the disease, as it acts on the underlying causes of type 2 diabetes, and not just lowers glucose levels. The use of the drug Avandia is indicated both as monotherapy to enhance the effectiveness of diet and exercise, and as part of a combined treatment in case of insufficient hypoglycemic effect of the maximum doses of metformin or sulfonylurea derivatives.

It should be noted that Avandia represents an extremely valuable new

therapeutic alternative in the struggle for adequate control of type 2 diabetes

Type 2 diabetes mellitus is a chronic pathology associated with impaired carbohydrate metabolism and the development of hyperglycemia. This results in insulin resistance and secretory dysfunction of beta cells. The cause of death is a cardiac or vascular pathology provoked by the ailment in question.

Medical indications

Pathology can develop at any age and in any gender. Indirect causes of type 2 diabetes, what it is, will be of interest to every patient. This list includes the following factors:

• excess weight;
• genes;
• ethnicity;
• passive lifestyle;
• malnutrition;

This is a multifactorial disease that is inherited. At the same time, hereditary predisposition to the disease depends on environmental factors and the person's lifestyle. Clinical heterogeneity is determined by a heterogeneous group of metabolic disorders.

This feature indicates the pathogenesis of type 2 diabetes mellitus, which is based on insulin resistance.

More often the disease proceeds without the expressed clinic. To make a diagnosis, the level of glycemia is taken into account. At the same time, the doctor listens to the patient's complaints, deciphers the diagnostic results. Symptoms of diabetes begin to appear after the age of 40. The main manifestation of the disease is obesity or metabolic syndrome.

The patient may complain of low performance, thirst. Rare symptoms of type 2 diabetes:

• allergy.

It will take several years for the above signs to appear. Therefore, patients with such a clinic are hospitalized in a surgical hospital with leg ulcers. Similar symptoms are the cause of the development of ophthalmic diseases. Patients with this diagnosis can be transferred to the cardiology department. Therapy is prescribed if the doctor has determined the stage of type 2 diabetes. This takes into account age, general condition of the body.

Complications and diagnosis of the disease

Acute consequences of NIDDM:

1. Hyperosmolar coma - glucose concentration exceeds 35 mmol / l. This condition is characterized by such manifestations as thirst, weakness, migraine. The patient may suffer from other symptoms. Additional signs of type 2 diabetes include low blood pressure and impaired consciousness. In this case, urgent medical attention is required.
2. Lactic acidosis - the concentration of lactic acid exceeds 4 mmol / l. This explains the fact why there is muscle and heart pain, shortness of breath.
3. Hypoglycemia - a low concentration of glucose is manifested, against which type 2 diabetes mellitus has the following symptoms: tremor, weakness, nervousness, pallor.

The pathology under consideration can provoke chronic complications, manifested in the form of diabetic ophthalmopathy and nephropathy, ischemia. Diagnosis begins with the detection of hyperglycemia in individuals with a typical clinic. In parallel, the patient's medical history is studied.

Obesity, problems with metabolism testify to sugar disease.

Diabetes may be indicated by the results of laboratory diagnostics, which is carried out after screening. The level of glycemia is assigned to the following persons:

• patients over 45 years of age;
• persons leading a passive life;
• overweight young people.

In patients most predisposed to non-insulin-dependent diabetes mellitus, the medical history is studied in detail. Therapy is prescribed after the diagnosis of the heart and blood vessels, determining the value of HDL. Since children are at risk, they are assigned the latest research - screenings. Such procedures are considered mandatory. In parallel, the doctor identifies the causes of type 2 diabetes. In the presence of some indications, additional diagnostics are carried out.

Therapy Methods

The treatment of two types of the disease includes:

• diet therapy;
• physical activity;
• hypoglycemic treatment of diabetes 2;
• prevention and treatment of late complications of the disease in question.

Since many patients with this diagnosis are obese, proper nutrition is indicated. It is necessary to give up fats. But in order for the therapy to be effective, before treating type 2 diabetes, a consultation with a nutritionist is prescribed. It is recommended to follow a hypocaloric diet. This disease requires the rejection of alcohol. Otherwise, hypoglycemia will occur.

To prevent atherosclerosis, modern methods of treatment are used. Medicine helps to heal with the help of swimming and walking. Physical activity should be individualized. In the first days of treatment, aerobics is performed. At the same time, moderate intensity and duration are observed (30 minutes a day). Further treatment for type 2 diabetes is a gradual increase in exercise. Types of exercises should be selected by a qualified specialist. This reduces insulin resistance. At the same time, drug therapy is carried out, during which the patient must comply with all the instructions of the attending physician.

How to get rid of type 2 diabetes forever is an interesting question. Timely treatment of an early illness is considered a possible elimination of symptoms. The patient may be prescribed the following medications:

• sensitizers;
• clays;
• acarbose.

Before taking them, it is recommended to pass laboratory tests. In case of intolerance to the components, other medicines are selected. Whether type 2 diabetes can be cured with sensitizers will be of interest to many. These drugs include Metformin and thiazolidinedione. The first drug suppresses gluconeogenesis in the liver, reduces insulin resistance. In type 2 diabetes, the patient can be cured by taking Metformin and additional agents. The pathology under consideration is long-term and life-long. Therefore, it is not removed. Perhaps a decrease in the manifestation of her clinical picture. Metformin can be drunk in patients with obesity and hyperglycemia.

But Metformin does not get rid of type 2 diabetes in pregnant women.

Taking other medications

Thiazolidines are y-receptor agonists. They activate glucose metabolism, against which the activity of endogenous insulin increases. This provokes an insulin-dependent disease. How to beat type 2 diabetes is interesting to most people. In such cases, the doctor prescribes the latest treatment: thiazolidinedione + Metformin. Contraindications to such modern treatment of type 2 diabetes mellitus are a 2.5-fold increase in the level of hepatic transaminases and edema.

Iglinides are used to eliminate the disease and enhance insulin secretion. They are recommended to drink after meals. Non-insulin-dependent diabetes mellitus of the 2nd degree requires the use of sulfonylurea drugs, which contribute to the closure of ATP-dependent potassium channels. But such therapy can provoke hypoglycemia. A side effect of this method of treating type 2 diabetes occurs after an overdose of iglinides, non-compliance with the diet. Repaglinide is an effective glinide.

To reduce the absorption of glucose in the intestines, Acarbose and Guar gum are taken. This is new in the treatment of type 2 diabetes, so these medications are taken under medical supervision. Acarbose blocks intestinal a-glycosidases, slowing down the fermentation and absorption of carbohydrates. What is needed to cure type 2 diabetes should be known to all people suffering from such a disease. It is recommended to take Acarbose before meals or during meals. In this case, the main negative side effect is tolerated - diarrhea. It develops against the background of the intake of unabsorbed carbohydrates into the intestine.

At the same time, a moderate hypoglycemic effect is observed.

Before you cure insulin-dependent diabetes mellitus, it is recommended to conduct laboratory diagnostics. Insulin medications can be prescribed in combination with hypoglycemic agents. Since the symptoms and treatment are interrelated, therefore, the choice of drugs is made taking into account the clinical picture. New treatments for type 2 diabetes (water pills) may be used. The patient may be prescribed Metformin + Stiazolidine + Dionam. Before prescribing drugs of this group, it is recommended to undergo a complete and comprehensive diagnosis.

Taking insulin and its analogs

How to cure type 2 diabetes with insulin preparations has its own nuances. Such funds are prescribed in 30-40% of cases. Indications for their reception:

• insulin deficiency;
• operation;
• stroke and other complications of type 2 diabetes;
• low glycemia;
• no permanent compensation;
• late stage of a chronic complication of the disease.

Whether the disease is cured in the latter case, that is what is of interest. With such a diagnosis, complex, but long-term treatment is indicated. Long-acting insulin therapy with an additional intake of a hypoglycemic agent is more often prescribed. If fasting glucose levels cannot be controlled with metformin, the patient is given an insulin injection. If insulin-dependent diabetes mellitus is not controlled by pills, minoinsulin therapy is performed.

The traditional scheme of therapy is more often used: a fixed dosage of short-acting and long-acting insulin. In this case, in type 2 diabetes, treatment includes the use of standard insulin mixtures. In this case, there is a risk of developing hypoglycemia. If the patient is under 30 years old, how to treat type 2 diabetes, it is worth learning more. In this case, it is recommended to be cured with an intensive version of insulin therapy. Particular attention is paid to children and pregnant women.

In severe cases, such patients are hospitalized.

Preventive measures

Whether type 2 diabetes can be cured is of interest to many. The disease in question is chronic, so it will occur throughout the life of the patient. Illness of any form and degree is not curable. You can only prevent the development of the second type of disease. To do this, it is recommended to change your lifestyle.

Particular attention is paid to weight support. You can find out about overweight using a special table with body mass indexes. If non-insulin-dependent diabetes is diagnosed, slight weight loss is recommended. To do this, you can do physical exercises. It is necessary to engage in a sport that increases the heart rate.

If regular physical exercises are prescribed for type 2 diabetes, then they are performed for 30 minutes, but daily. Some patients can do resistive exercises (weight lifting). If the patient is at risk for type 2 diabetes, is it curable, that's what's interesting. Elimination of the symptoms of the disease is allowed if:

• pathology detected in a timely manner;
• prescribed adequate therapy;
• no comorbidities;
• normal general condition of the patient.

How to prevent complications of type 2 diabetes mellitus is a hot topic. To do this, you need to maintain normal blood sugar levels. The doctor will tell you the optimal dosage of aspirin to prevent a stroke. At the same time, blood pressure and cholesterol are controlled. If nephropathy manifests itself, it is required to take ACE or angiotensin 2. It is important to detect it at an early stage for the prevention and timely treatment of the disease. For this, routine screening studies of fasting blood sugar levels are carried out.

In a healthy person, the hormone insulin opens the "doors" in the walls of cells, passing through them glucose from the bloodstream, which is so necessary for the body to receive energy. In a patient with type 2 diabetes, the cells resist the effects of insulin on them. Rejection of insulin by cells does not allow glucose to penetrate into them in the right amount.

Pathogenesis (causes) of type 2 diabetes mellitus

The characteristic cause of type 2 diabetes, insulin resistance, is mainly due to obesity, which makes it difficult for glucose to enter the cells, since they are already filled with fat. Initially, pancreatic cells have the ability to overcome this resistance by producing more insulin. But over time, they are no longer able to produce as much insulin as they need. In diabetes, even elevated due to the compensatory reaction of the body, the level of insulin is not able to open the "doors" of the cells, as a result of which glucose begins to accumulate in the blood. Being overweight also increases the risk of type 2 diabetes etiology, high blood pressure and heart disease can also be causes.

The vast majority of diabetics have type 2 diabetes, mainly the cause is overweight or the age of the patient is more than forty years. A sedentary lifestyle, physical inactivity can also be one of the pathogenesis of type 2 diabetes. Regular exercise helps to avoid a greater risk of this disease.

Etiology of type 2 diabetes

There is also an important genetic component in the etiology of type 2 diabetes. The more relatives of a person suffered from this disease, the higher his predisposition to this disease. But despite the strong genetic influence, the pathogenesis of type 2 diabetes can be avoided by maintaining a healthy, normal weight.

Some women who do not normally have diabetes experience an increase in blood sugar levels during pregnancy. This form of the disease is called gestational diabetes.

Thus, the following risk factors for the pathogenesis of type 2 diabetes can be distinguished:

• heredity,
• obesity,
• impaired glucose tolerance (an individual feature of the body that can be detected during an oral glucose tolerance test),
• diabetes during pregnancy, the so-called gestational diabetes, as well as the birth of a large child (from 3.6 kg or more).

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Type 2 diabetes- a chronic disease manifested by a violation of carbohydrate metabolism with the development of hyperglycemia due to insulin resistance and secretory dysfunction of β-cells, as well as lipid metabolism with the development of atherosclerosis. Since the main cause of death and disability of patients are complications of systemic atherosclerosis, CD-2 is sometimes called a cardiovascular disease.

Table 1

Type 2 diabetes

Etiology

CD-2 is a multifactorial disease with a hereditary predisposition. Concordance for CD-2 in identical twins reaches 80% or more. Most patients with CD-2 indicate the presence of CD-2 in the next of kin; in the presence of CD-2 in one of the parents, the probability of its development in the offspring throughout life is 40%. No one gene, the polymorphism of which determines the predisposition to CD-2, has been found. Of great importance in the implementation of a hereditary predisposition to CD-2 is played by environmental factors, primarily lifestyle features. Risk factors for the development of CD-2 are:

• obesity, especially visceral;
• ethnicity (especially when changing the traditional way of life to the western one);
• CD-2 in the next of kin;
• sedentary lifestyle;
• dietary features (high consumption of refined carbohydrates and low fiber content);
• arterial hypertension.

Pathogenesis

Pathogenetically, CD-2 is a heterogeneous group of metabolic disorders, and this is precisely what determines its significant clinical heterogeneity. Its pathogenesis is based on insulin resistance (a decrease in insulin-mediated glucose utilization by tissues), which is realized against the background of secretory dysfunction of β-cells. Thus, there is an imbalance between insulin sensitivity and insulin secretion. The secretory dysfunction of β-cells is to slow down the "early" secretory release of insulin in response to an increase in blood glucose levels. At the same time, the 1st (fast) phase of secretion, which consists in emptying the vesicles with accumulated insulin, is virtually absent; The 2nd (slow) phase of secretion is carried out in response to stabilizing hyperglycemia constantly, in a tonic mode, and, despite excessive secretion of insulin, the level of glycemia against the background of insulin resistance does not normalize (Fig. 1).

Rice. 1. Secretory dysfunction of beta cells in type 2 diabetes mellitus (loss of the 1st fast phase of insulin secretion)

The consequence of hyperinsulinemia is a decrease in the sensitivity and number of insulin receptors, as well as suppression of post-receptor mechanisms that mediate the effects of insulin ( insulin resistance). The content of the main glucose transporter in muscle and fat cells (GLUT-4) is reduced by 40% in visceral obese people and by 80% in people with DM-2. Due to insulin resistance of hepatocytes and portal hyperinsulinemia, overproduction of glucose by the liver, and fasting hyperglycemia develops, which is detected in most patients with DM-2, including in the early stages of the disease.

By itself, hyperglycemia adversely affects the nature and level of secretory activity of β-cells (glucose toxicity). Long-term, over many years and decades, existing hyperglycemia eventually leads to the depletion of insulin production by β-cells and the patient may develop some symptoms. insulin deficiency- weight loss, ketosis with concomitant infectious diseases. However, residual insulin production, which is sufficient to prevent ketoacidosis, is almost always preserved in DM-2.

Dedov I.I., Melnichenko G.A., Fadeev V.F.