Basic research. Mechanisms of occurrence and development of diabetes mellitus The role of obesity and physical inactivity

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Type 2 diabetes— chronic illness, 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.

For successful treatment diabetes a prerequisite is the impact on all the components of its pathogenesis. Scientists have been studying the causes and mechanisms of diabetes for many years, and a number of pathophysiological processes and etiological factors have already been established that lead to hyperglycemia as a result.

What triggers diabetes

Diabetes mellitus is a heterogeneous pathology in which a complex of metabolic disorders develops. Main characteristics type 2 diabetes is insulin resistance and poor function of beta cells of varying severity.

Modern scientific research has shown that many factors are involved in the development of diabetes mellitus and a significant role in the development this disease played by external, non-genetic factors.

It has now been proven that the following factors play a major role in the pathogenesis of type 2 diabetes:

• hereditary predisposition - diabetes mellitus in parents, close relatives;
• unhealthy lifestyle - bad habits, low degree of physical activity, chronic fatigue, frequent stress;
• food - high-calorie and leading to obesity;
• insulin resistance - a violation of the metabolic response to insulin;
• violation of insulin production and increased production of glucose by the liver.

The role of individual etiological factors in the pathogenesis of diabetes

The pathogenesis of diabetes mellitus depends on the type. In type 2 diabetes, it includes hereditary and external factors. In fact, genetic factors are more important in type 2 diabetes than in type 1 diabetes. This conclusion is based on a study of twins.

It used to be thought that identical (monozygous) twins had an incidence of type 2 diabetes of about 90-100%.

However, with the use of new approaches and methods, it has been proven that concordance (coincidence in the presence of the disease) in monozygotic twins is slightly lower, although it remains quite high 70-90%. This indicates a significant contribution of heredity in the predisposition to type 2 diabetes.

Genetic predisposition is important in the development of prediabetes (impaired glucose tolerance). Whether a person develops diabetes further depends on their lifestyle, diet, and other external factors.

The role of obesity and physical inactivity

Frequent overeating and a sedentary lifestyle lead to obesity and further exacerbate insulin resistance. This contributes to the implementation of the genes responsible for the development of type 2 diabetes.

Obesity, especially abdominal obesity, plays a special role not only in the pathogenesis of insulin resistance and the resulting metabolic disorders, but also in the pathogenesis of type 2 diabetes.

This is because visceral adipocytes, in contrast to subcutaneous adipose tissue adipocytes, are less sensitive to the anti-lipolytic action of the hormone insulin and more sensitive to the lipolytic action of catecholamines.

This circumstance causes the activation of lipolysis of the visceral fat layer and the entry, first into the bloodstream of the portal vein, and then into the systemic circulation, of a large amount of free fatty acids. In contrast, the cells of the subcutaneous fat layer to slow down the action of insulin, it promotes the reesterification of free fatty acids to triglycerides.

Insulin resistance of skeletal muscles lies in the fact that they preferentially utilize free fatty acids at rest. This prevents myocytes from utilizing glucose and leads to an increase in blood sugar and a compensatory increase in insulin. Moreover, fatty acids do not allow insulin to bind to hepatocytes, and this exacerbates insulin resistance at the liver level and inhibits the inhibitory effect of the hormone on gluconeogenesis in the liver. Gluconeogenesis leads to a constant increased production of glucose in the liver.

Thus, a vicious circle is created - an increase in the level of fatty acids causes even greater insulin resistance of muscle, adipose and liver tissue. It also leads to the launch of lipolysis, hyperinsulinemia, and hence to an increase in the concentration of fatty acids.

Insufficient physical activity in type 2 diabetics exacerbates existing IR.

At rest, the transfer of glucose transporter substances (GLUT-4) in myocytes is sharply reduced. Muscle contraction during physical activity increases the delivery of glucose to myocytes, this is due to an increase in the translocation of GLUT-4 to the cell membrane.

Causes of insulin resistance

Insulin resistance in type 2 diabetes mellitus is a condition in which there is an insufficient biological response of tissues to insulin at its normal concentration in the blood. In the study of genetic defects that cause the presence of insulin resistance, it was found that it mainly occurs against the background of the normal functioning of insulin receptors.

Insulin resistance is associated with insulin dysfunction at the receptor, pre-receptor and post-receptor levels. Receptor insulin resistance is associated with an insufficient number of receptors on the cell membrane, as well as a change in their structure. Prereceptor insulin resistance is caused by a disorder in the early stages of insulin secretion and (or) with a pathology of the conversion of proinsulin to C-peptide and insulin. Post-receptor insulin resistance includes a defect in the activity of transducers that signal insulin within the cell, as well as those involved in protein synthesis, glycogen, and glucose transport.

The most important consequences of insulin resistance are hyperinsulinemia, hyperglycemia, and dyslipoproteinemia. In disruption of insulin production, hyperglycemia plays a leading role and leads to its gradual relative deficiency. In patients with type 2 diabetes, the compensatory capacity of pancreatic beta cells is limited due to the genetic breakdown of glucokinase and the glucose transporter GLUT-2. These substances are responsible for the production of insulin for glucose stimulation.

Insulin production in type 2 diabetics

In patients with type 2 diabetes, insulin secretion is usually impaired. Namely:

• a delayed initial phase of the secretory response to intravenous glucose loading;
• reduced and delayed secretory response to the use of mixed food;
• elevated levels of proinsulin and products of its processing;
• the rhythm of fluctuations in insulin secretion is disturbed.

Among possible causes disorders of insulin production can be called both primary genetic defects in beta cells, and secondary developing disorders due to lipo - and glucose toxicity. There are studies aimed at finding out other causes of impaired insulin secretion.

In the study of insulin production in patients with prediabetes, it was found that even before the increase in fasting sugar levels and with normal levels of glycosylated hemoglobin, the rhythm of fluctuations in insulin production is already disturbed. This consists in reducing the ability of pancreatic beta cells to respond with peak insulin secretion to peak fluctuations in blood glucose concentration throughout the day.

Moreover, obese patients with insulin resistance produce more insulin in response to the same amount of glucose than healthy people with normal weight and without insulin resistance. This means that in people with prediabetes, insulin secretion is already deficient, and this is important for the development of type 2 diabetes in the future.

Early stages of impaired insulin secretion

Changes in insulin secretion in prediabetes occur due to increased concentrations of free fatty acids. This, in turn, leads to inhibition of pyruvate dehydrogenase, and hence to a slowdown in glycolysis. Inhibition of glycolysis leads in beta cells to a decrease in the formation of ATP, which is the main trigger for insulin secretion. A role for glucose toxicity in a defect in insulin secretion in prediabetic patients (impaired glucose tolerance) is ruled out because hyperglycemia has not yet been observed.

Glucose toxicity is a set of bimolecular processes in which prolonged excess concentration of glucose in the blood leads to damage to insulin secretion and tissue sensitivity to it. This is another vicious circle in the pathogenesis of type 2 diabetes. It can be concluded that hyperglycemia is not only the main symptom, but also a factor in the progression of type 2 diabetes due to the action of the phenomenon of glucose toxicity.

With prolonged hyperglycemia, a decrease in insulin secretion is observed in response to a glucose load. At the same time, the secretory response to stimulation with arginine remains, on the contrary, enhanced for a long time. All of the above problems with insulin production are corrected while maintaining a normal blood sugar concentration. This proves that the phenomenon of glucose toxicity plays an important role in the pathogenesis of defective insulin secretion in type 2 diabetes.

Also, glucose toxicity leads to a decrease in tissue sensitivity to insulin. Thus, achieving and maintaining normal blood glucose levels will increase the sensitivity of peripheral tissues to the hormone insulin.

The pathogenesis of the main symptom

Hyperglycemia is not only a marker of diabetes, but also the most important link in the pathogenesis of type 2 diabetes.

It disrupts insulin secretion by pancreatic beta cells and glucose uptake by tissues, which aims to correct carbohydrate metabolism disorders in patients with type 2 diabetes mellitus to normoglycemia.

An increase in fasting sugar is early symptom type 2 diabetes, which is caused by increased sugar production by the liver. The severity of insulin secretion disorders at night directly depends on the degree of fasting hyperglycemia.

Insulin resistance of hepatocytes is not a primary breakdown, it appears as a result of the influence of metabolic and hormonal disorders, including an increase in glucagon production. In chronic hyperglycemia, beta cells lose their ability to respond to rising blood glucose levels by decreasing glucagon secretion. As a result, hepatic glycogenolysis and gluconeogenesis increase. This is one of the factors of relative insulin deficiency in the portal blood circulation.

An additional reason for the development of insulin resistance at the liver level is the inhibitory effect of fatty acids on the uptake and internalization of insulin by hepatocytes. Excessive intake of free fatty acids into the liver sharply stimulates gluconeogenesis due to an increase in the production of acetyl-CoA in the Krebs cycle.

Moreover, acetyl-CoA, in turn, reduces the activity of the enzyme pyruvate dehydrogenase. The result of this is excess secretion of lactate in the Cori cycle (lactate is one of the main products for gluconeogenesis). Fatty acids also inhibit the activity of the glycogen synthase enzyme.

Role in the pathogenesis of type 2 diabetes mellitus amylin and leptin

Recently, the substances amylin and leptin play a significant role in the mechanism of development of type 2 diabetes. The role of amylin was established only 15 years ago. Amylin is an islet amyloid polypeptide that resides in the secretory granules of beta cells and is normally produced together with insulin in a ratio of approximately 1:100. The content of this substance is increased in patients with insulin resistance and impaired carbohydrate tolerance (prediabetes).

In type 2 diabetes, amylin accumulates in the islets of Langerhans as amyloid. It is involved in the regulation of carbohydrate metabolism by adjusting the rate of absorption of glucose from the intestines, and inhibiting the production of insulin in response to glucose irritation.

In the last 10 years, the role of leptin in the pathology of fat metabolism and the development of type 2 diabetes has been studied. Leptin is a polypeptide produced by white adipose tissue cells and acts on the nucleus of the hypothalamus. Namely, on the ventro-lateral nuclei responsible for eating behavior.

Leptin secretion decreases during fasting and increases during obesity, in other words, it is regulated by the adipose tissue itself. A positive energy balance is associated with an increase in the production of leptin and insulin. The latter interact with the hypothalamic centers, most likely through the secretion of the hypothalamic neuropeptide Y.

Fasting leads to a decrease in the amount of adipose tissue and a decrease in the concentration of leptin and insulin, which stimulates the secretion of the hypothalamic neuropeptide Y by the hypothalamus. This neuropeptide controls eating behavior, namely, causes strong appetite, weight gain, accumulation of body fat, and inhibition of the sympathetic nervous system.

Both relative and absolute insufficiency of leptin leads to an increase in the secretion of neuropeptide Y, and hence to the development of obesity. With an absolute deficiency of leptin, its exogenous administration, in parallel with a decrease in appetite and weight, reduces the content of mRNA that encodes neuropeptide Y. Exogenous administration of leptin with its relative deficiency (as a result of a mutation of the gene that encodes its receptor) does not affect weight.

It can be assumed that the absolute or relative deficiency of leptin leads to the loss of inhibitory control over the secretion of the hypothalamic neuropeptide Y. This is accompanied by autonomic and neuroendocrine pathologies that are involved in the development of obesity.

The pathogenesis of type 2 diabetes is a very complex process. It plays a major role in insulin resistance, violation of insulin production and chronic increased secretion of glucose by the liver. When selecting treatment to achieve compensation for type 2 diabetes and prevent complications, this should be taken into account.

FROM According to modern concepts, it is due to two key mechanisms: the development of insulin resistance (a decrease in insulin-mediated glucose utilization by tissues) of peripheral target tissues and insulin hypersecretion, which is necessary to overcome the barrier of insulin resistance.

Insulin resistance is genetically determined and is the main risk factor for the development of diabetes mellitus, however, a significant decrease in the secretory capacity of the pancreatic insular apparatus causes postprandial hyperglycemia by inducing oxidative stress, leading to B-cell apoptosis, i.e. the development of the phenomenon of "glucose toxicity", which stimulates the rapid depletion of the capabilities of the insular apparatus. The UKPDS study (United Kingdom Prospective Diabetes Study) showed that already by the clinical debut of the disease, insulin secretion in patients is reduced by an average of 50%. This phenomenon causes an earlier manifestation of type 2 diabetes.

On the initial stages the disease is asymptomatic because insulin resistance is compensated by hyperinsulinemia, which helps maintain normal carbohydrate tolerance. Later this mechanism is depleted, and the liver overproduces glucose, which leads to fasting hyperglycemia. In addition, insulin resistance, hyperinsulinemia and lipid metabolism disorders also lead to a violation in the blood coagulation system, contributing to the development of a procoagulant state.

Compensatory hyperinsulinemia, aimed at overcoming insulin resistance, forms a "vicious circle", leading to increased appetite and weight gain.

An increase in body weight above normal levels, in turn, exacerbates insulin resistance and, accordingly, additionally stimulates insulin secretion, which inevitably leads to depletion of the secretory capacity of pancreatic B-cells. The resulting violation of carbohydrate tolerance manifests itself as postprandial hyperglycemia. The manifestation of diabetes mellitus is associated with the secretory failure of pancreatic B-cells in overcoming insulin resistance (Fig. 1.)

In addition, a violation of the normal rhythm of insulin secretion plays a role in the development of type 2 diabetes mellitus. The mechanisms of development of secretory dysfunction of β-cells of the islets of Langerhans in type 2 diabetes are characterized by:

hyperinsulinemia with no fluctuations in insulin levels;

lack of the 1st phase of insulin secretion,

In the 2nd phase, insulin secretion is carried out in response to stabilizing hyperglycemia in the tonic mode, despite excessive secretion of insulin (see Figure 2.);

The level of glucagon secretion increases with an increase in glycemia and decreases with hypoglycemia;

· premature emptying of "immature" vesicles of β-cells with the release of insufficiently formed proinsulin, which has an atherogenic effect in the development of atherosclerosis in metabolic syndrome.

Violation of insulin secretion in response to glucose stimulation: the early peak of insulin secretion characteristic of normal function of β-cells disappears at an initially higher level of basal secretion. As a result, the total amount of insulin does not decrease, but even exceeds normal values. At the same time, the insufficiency of the first phase of insulin secretion is a fact that makes it possible to explain the development and persistence of hyperglycemia with normal fasting blood glucose (i.e. impaired glucose tolerance).

Today, the third pathogenetic factor in the development of type 2 diabetes is isolated - a defect in the secretion of incretins - hormones produced by L-cells and the small and large intestine and through specific receptors acts on pancreatic β- and α-cells, the gastrointestinal tract, the central nervous system, thyroid gland and heart: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. The secretion of incretins is the result of nutritional stimulation of the proximal intestine and is mediated by stimulation of insulin secretion and inhibition of glucagon secretion. The level of GLP-1 in type 2 DM is significantly lower than in healthy people, which contributes to the development of postprandial hyperglycemia and other disorders. At the same time, the action of endogenous GLP-1 is limited by the high activity of the dipeptidyl-peptidase 4 (DPP-4) enzyme, which causes cleavage of the molecule within 3–5 minutes.

Type 2 DM develops slowly, with a gradual increase in the degree of β-cell dysfunction in most cases against the background of severe IR caused by overweight and visceral obesity and persisting throughout the patient's subsequent life (Fig. 3). Background IR exacerbates β-cell dysfunction and causes a gradual development and increase in relative insulin deficiency. In parallel, a violation of fasting glycemia, impaired glucose tolerance and chronic hyperglycemia develop. Currently, it is accepted to combine impaired fasting glycemia and impaired glucose tolerance into the general concept of "prediabetes", which, in the absence of intervention preventive measures leads in 70% to the development of manifest type 2 diabetes within 3 years.

Fig.3. Stages of development of type 2 diabetes

Sequence of development pathological conditions(prediabetes and overt type 2 diabetes) determines and substantiates the sequence and tactics of choosing hypoglycemic drugs.

Diabetes is a group of metabolic diseases that share a common feature - chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Chronic hyperglycemia in diabetes mellitus is combined with damage, dysfunction and development of insufficiency of various organs, especially the eyes, kidneys, and nervous system.

Etiological classification of glycemic disorders(WHO, 1999)

1 type(due to the destruction of beta cells, usually leads to absolute insulin deficiency): autoimmune, idiopathic.

2 types(may range from a predominance of insulin resistance with relative insulin deficiency to a predominance of defects in insulin secretion with or without insulin resistance)

Gestational diabetes mellitus

Other specific types:

Genetic defects that cause dysfunction of beta cells;

Genetic defects that cause impaired insulin action;

Diseases of the exocrine part of the pancreas;

endocrinopathy;

Induced by pharmacological and chemical agents;

infections;

Rare forms of immune-mediated diabetes;

Other genetic syndromes sometimes associated with diabetes

Genetic defects in beta cell function:

1.MODY-3 (chromosome 12, HNF-1a); 2.MODY-2 (chromosome 7, glucokinase gene); 3.MODY-1 (chromosome 20, gene HNF-4a); 4. Mitochondrial DNA mutation; 5.Others

Genetic defects that cause impaired insulin action:

1. Resistance to type A insulin; 2.Leprechaunism; 3. Rabson-Mendehall syndrome; 4. Lipoatrophic diabetes; 5.Others

Diseases of the exocrine pancreas:

1. Pancreatitis; 2. Trauma (pancreatectomy); 3. Neoplasia; 4. Cystic fibrosis

5. Hemochromatosis; 6. Fibrocalculous pancreatopathy

Endocrinopathy: 1. Acromegaly; 2. Cushing's syndrome; 3. Glucagonoma; 4. Pheochromocytoma; 5. Thyrotoxicosis; 6. Somatostatinoma; 7.Aldosteroma; 8.Others

Diabetes mellitus induced by pharmacological and chemical agents: 1.Vakor; 2. Pentamidine; 3. Nicotinic acid; 4. Glucocorticoids; 5. Thyroid hormones; 6. Diazoxide; 7. Alpha-adrenergic agonists; 8. Thiazides; 9.Dilantin; 10.A - Interferon; 11.Others

Infections: 1. Congenital rubella; 2. Cytomegalovirus; 3.Others

Unusual forms of immune-mediated diabetes

1. "stiff-man" - syndrome (syndrome of immobility); 2. Autoantibodies to insulin receptors; 3.Others

Other genetic syndromes sometimes associated with diabetes include:

1. Down syndrome; 2. Klinefelter's syndrome; 3. Turner's syndrome; 4. Wolfram syndrome; 5. Friedreich's syndrome; 6.Hentingten's chorea; 7. Lawrence-Moon-Beadle syndrome; 8. Miotic dystrophy; 9.Porphyria; 10. Prader-Ville syndrome; 11.Others

Type 1 diabetes reflects the destruction of beta cells, which always leads to the development of diabetes mellitus, in which insulin is required for survival in order to prevent the development of ketoacidosis, coma and death. Type one is usually characterized by the presence of antibodies to GAD (glutamate decarboxylase), beta cell (ICA) or insulin, which confirm the presence of an autoimmune process.

Stages of development of type 1 diabetes (EisenbarthG. S , 1989)

1 stage-genetic predisposition, which is realized in less than half of genetically identical twins and in 2-5% of siblings. Of great importance is the presence of HLA antibodies, especially the second class -DR 3 ,DR 4 and DQ. At the same time, the risk of developing type 1 diabetes mellitus increases many times over. In the general population - 40%, in patients with diabetes mellitus - up to 90%.

3 stage-stage of immunological disorders- maintains normal insulin secretion. Immunological markers of type 1 diabetes mellitus are determined - antibodies to beta cell antigens, insulin, GAD (GAD is determined for 10 years.)

4 stage-stage of severe autoimmune disorders characterized by a progressive decrease in insulin secretion due to the development of insulitis. The level of glycemia remains normal. There is a decrease in the early phase of insulin secretion.

5 stage-stage of clinical manifestation develops with the death of 80-90% of the mass of beta cells. At the same time, residual secretion of the C-peptide is preserved.

Type 2 diabetes- a heterogeneous disease, which is characterized by a complex of metabolic disorders, which are based on insulin resistance and a dysfunction of beta cells of varying severity.

Etiology of type 2 diabetes.

Most forms of type 2 diabetes are polygenic in nature; a certain combination of genes that determines the predisposition to the disease, and its development and clinic are determined by such non-genetic factors as obesity, overeating, sedentary lifestyle, stress, as well as insufficient nutrition in the womb and in the first year of life.

The pathogenesis of type 2 diabetes mellitus.

According to modern concepts, two mechanisms play a key role in the pathogenesis of type 2 diabetes: 1. violation of insulin secretion beta cells; 2. increased peripheral resistance to the action of insulin (decrease in peripheral glucose uptake by the liver or increase in glucose production).). It is not known what develops first - a decrease in insulin secretion or insulin resistance, perhaps the pathogenesis is different in different patients. Most often, insulin resistance develops with obesity, more rare causes are presented in the table.

Type 2 diabetes mellitus pathogenesis (insulin secretion and insulin resistance)

Pathophysiological, clinical and genetic differences between types 1 and 2 diabetes are presented in Table 1.

P Lifestyle and nutritionAtogenesis of type 2 diabetes mellitus

R

Increased production of glucose liver

Obesity