Mechanisms of occurrence and development of diabetes mellitus. Basic research Etiology and pathogenesis

Diabetes mellitus is a pathological condition in which relative or absolute insulin deficiency develops, leading to phenomena such as hyperglycemia and glycosuria. The disease is accompanied by severe metabolic disturbances and the frequent development of complications. For proper treatment of this disease, it is important to understand the causes of its occurrence, as well as the mechanisms of development. Therefore, if such a diagnosis is made, the etiology, pathogenesis, and clinical treatment are interconnected.

The role of the pancreas in glucose metabolism

The etiology and pathogenesis of diabetes mellitus can be better understood if we consider the characteristics of carbohydrate metabolism in the human body and the role that active substances secreted by the pancreas play in it.

The pancreas, or pancreas, is an organ that has exocrine and endocrine activities. It received this name due to the fact that it is located behind the stomach. Many vessels and nerves pass through the pancreas.

The endocrine part of the organ is represented by the islets of Langerhans, which constitute 1 to 3% of the total tissue in a normal person. The islets have several types of cells, including alpha cells that produce glucagon and beta cells that produce insulin.

In the 20s of the last century, scientists isolated insulin, and this became a big breakthrough in the treatment of diabetes, since before that such patients simply died. It was found that the active substance in the form of insulin, under the influence of biochemical processes, arises from its predecessor, proinsulin, by the method of cleavage of the C-peptide from it. As a result, the same amount of both substances enters the blood. This served as the basis for the laboratory determination of C-peptide as an indicator of the ability of beta cells to produce insulin.

Not long ago, scientists determined that C-peptide also has a certain degree of activity and is involved in the following processes:

Decreased glycated hemoglobin.

Stimulation of glucose uptake by muscle tissue.

Reducing insulin resistance, and thereby enhancing the effects of insulin.

Reducing the likelihood of developing neuropathy.

Improves the filtration function of the kidneys and strengthens the retina.

The body normally needs to secrete about 50 units of insulin per day. In the normal state of the organ, the pancreas has from 150 to 250 units. The released insulin enters the hepatocytes through the portal vein system. There it undergoes partial inactivation with the participation of the enzyme insulinase. The remaining active part of the substance binds to proteins, and in a certain amount remains unbound. The proportions of bound and free insulin are regulated depending on the amount of sugar in the blood. Free insulin is normally intensively formed during hyperglycemia.

In addition to the liver, insulin is broken down in the kidneys, adipose tissue, muscles and the placenta. The formation of this hormone normally depends on the level of glucose, for example, with an excess of sweets in the food consumed, it causes increased work of insulin-producing cells. A decrease or increase in insulin in the blood can be caused by other factors and hormonal substances, but the main regulation depends on the intake of sugars from food.

How does insulin work?

In a disease such as diabetes mellitus, the etiology and pathogenesis lie in certain factors that contribute to impaired insulin production, or the lack of response of peripheral tissues to its action.

On the cells of some tissues there are special types of receptors through which glucose is transported. Insulin joins them and speeds up the absorption process by 20-40 times.

Etiology and pathogenesis of diabetes mellitus

Diabetes mellitus, according to the classification, is divided into types 1 and 2 (insulin-dependent and non-insulin-dependent). There are also other types of disease - gestational (during pregnancy), some specific conditions, genetic defects that cause disturbances in sugar metabolism. Diabetes is noted separately, developing as a result of other endocrine pathologies (thyrotoxicosis, Cushing's syndrome, etc.), disease as a result of exposure to pharmacological and chemical substances, and some syndromes that may be accompanied by diabetes mellitus (Down, Friedreich, etc.).

The main ones are the first two types of the disease, each of which has its own development characteristics and causes.

Etiology of type 1 diabetes mellitus

Insulin-dependent diabetes mellitus is considered an autoimmune disease in which beta cells located in the pancreas are damaged. Their main function is the production of insulin. In type 1 diabetes, there is a decrease or cessation of its production and the development of absolute insulin deficiency. It is observed in young people with rapid development of clinical symptoms.

The development of this variant of the disease is associated with a hereditary predisposition. However, confirmation of this appears only in a third of patients. In this case, antibodies to glutamate decarboxylase, beta cells, or directly to insulin are detected. And this is the main evidence of an autoimmune process.

A high probability of the disease manifesting itself exists in the presence of other autoimmune pathologies, both those associated with endocrine organs (Addison's disease, autoimmune thyroiditis) and others (Crohn's disease, rheumatism, vitiligo).

Pathogenesis of type 1 diabetes mellitus

If there is a predisposition to this type of disease, after the emergence of a situation that triggers the process, type 1 diabetes develops. Such mechanisms are:

Viral, bacterial or fungal infection;

Stressful situation;

Violation of the regime and quality of food intake;

Intoxication of non-infectious origin (including when using certain medications);

Irradiation.

Under the influence of the trigger mechanism, antibodies begin to be intensively produced; in the initial stage, insulin production remains within normal limits. In a disease such as type 1 diabetes, pathogenesis is characterized by the onset of massive destruction of beta cells due to the aggressive influence of the patient’s own antibodies. But even in this case, the blood glucose level does not change for some time. The strengthening of the autoimmune reaction is also due to the fact that when exposed to diabetogenic factors, the amount of free radicals increases. They lead to increased damage to beta cells.

Clinical manifestations, which determine the pathogenesis of the main symptoms of diabetes mellitus, begin to develop when about 80-90% of insulin-producing cells die. In such patients, insulin administration is vital to prevent the development of hyperglycemia, ketoacidosis and death.

Diabetes mellitus type 2 etiology

The non-insulin-dependent form of diabetes is determined by metabolic disorders with the development of insensitivity of tissue receptors to insulin and changes to varying degrees in the functioning of beta cells. It is detected mainly in middle-aged and elderly people; the increase in symptoms occurs more slowly than with the insulin-dependent type of the disease.
The etiology of type 2 diabetes mellitus is that, against the background of a hereditary tendency to develop and under the influence of eating disorders, overeating, weight gain, a stressful situation, as well as as a result of malnutrition, metabolic disorders develop in the womb and in the first year after birth glucose.

Pathogenesis of type 2 diabetes mellitus

Modern data suggest that the pathogenesis of type 2 diabetes mellitus is an increase in resistance to the action of insulin in peripheral tissues, which most often occurs with abdominal obesity and disruption of the pancreas cells that produce insulin. When a disease such as diabetes mellitus is detected in children, the pathogenesis and causes of such a disease are no different from those in adults. A feature of the disease in children is that they predominantly develop type 1 diabetes, and it is much more severe than in mature patients.

Insulin resistance can be hepatic or peripheral. When switching to replacement therapy, there is a decrease in glucose production in the liver, but such treatment in no way affects insulin sensitivity in peripheral tissues.

To improve the condition of this form of diabetes in the initial stage, weight loss, increased physical activity, and adherence to a low-carbohydrate and low-calorie diet are sufficient. Subsequently, glucose-lowering drugs of various mechanisms of action are used, and, if necessary, insulin.

- a chronic disease resulting from insulin resistance and relative insulin deficiency.

Etiology of type 2 diabetes mellitus

A multifactorial disease with a hereditary predisposition (if one of the parents has type 2 diabetes, the probability of its development in offspring throughout life is 40%.)

Risk factors for developing type 2 diabetes are:

1. Obesity, especially visceral
2. Ethnicity
3. Sedentary lifestyle
4. Nutritional Features
5. Arterial hypertension

Pathogenesis of type 2 diabetes mellitus

The basis is secretory dysfunction of beta cells, which consists of slowing the early secretory release of insulin in response to an increase in blood glucose levels.

In this case, the 1st (fast) phase of secretion, which consists of emptying vesicles with accumulated insulin, is virtually absent, and the 2nd (slow) phase of secretion occurs in response to stabilizing hyperglycemia constantly, in a tonic mode, and despite excess insulin secretion , the level of glycemia does not normalize against the background of insulin resistance.

The consequence of hyperinsulemia 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).

Hyperglycemia itself adversely affects the nature and level of secretory activity of beta cells - glucose toxicity. Long-term, over many years and decades, existing hyperglycemia ultimately leads to depletion of insulin production by beta cells and the patient develops some symptoms of insulin deficiency - weight loss, ketosis with concomitant infectious diseases.

As a result, we can distinguish 3 levels:

1. impaired insulin secretion
2. peripheral tissues become resistant
3. glucose production increases in the liver

Diagnostics type 2 diabetes mellitus

1. Fasting glucose measurement (three times).
   The normal glucose level in fasting blood plasma is up to 6.1 mmol/l.
   If from 6.1 to 7.0 mmol/l – impaired fasting glucose.
   More than 7 mmol/l – diabetes mellitus.
2. Glucose tolerance test. It is carried out only if the results are questionable, that is, if glucose is from 6.1 to 7.0 mmol/l.
   14 hours before the test, fasting is prescribed, then blood is taken - the initial glucose level is established, then the patient is given 75 grams of glucose dissolved in 250 ml of water to drink. After 2 hours, they take blood and look:
   - if less than 7.8, then normal glucose tolerance.
   - if from 7.8-11.1 then impaired glucose tolerance.
   - if more than 11.1 then SD.
3. Determination of C-peptide is necessary for differential diagnosis. If type 1 diabetes, then the level of C-peptide should be closer to 0 (from 0-2); if above 2, then type 2 diabetes.
4. Study of glycosylated hemoglobin (an indicator of carbohydrate metabolism over the last 3 months). The norm is less than 6.5% up to 45 years of age. After 45 years to 65 - 7.0%. After 65 years – 7.5-8.0%.
5. Determination of glucose in urine.
6. Acetone in urine, Lange test.
7. UAC, OAM, BH, glycemic profile.

Clinical manifestations type 2 diabetes mellitus

Gradual onset of the disease. Symptoms are mild (no tendency to ketoacidosis). Frequent combination with obesity (80% of patients with diabetes) and arterial hypertension.
The disease is often preceded by insulin resistance syndrome (metabolic syndrome): obesity, hypertension, hyperlipidemia and dyslipidemia (high concentration of triglycerides and low concentration of HDL cholesterol), and often hyperuricemia.

1. Hyperglycemia syndrome (polydipsia, polyuria, itchy skin, weight loss of 10-15 kg over 1-2 months. Severe general and muscle weakness, decreased performance, drowsiness. At the onset of the disease, some patients may experience an increase in appetite)
2. Glucosuria syndrome (glucose in urine.)
3. Acute complications syndrome
4. Late chronic complications syndrome.

Treatment type 2 diabetes mellitus

Treatment of type 2 diabetes consists of 4 components: diet therapy, physical activity, administration of oral hypoglycemic drugs, and insulin therapy.
Treatment Goals
■ The main goal of treatment for patients with type 1 diabetes is glycemic control.
■ Maintaining the level of glycosylated hemoglobin.
■ Normalization of general condition: control of height, body weight, puberty, monitoring of blood pressure (up to 130/80 mm Hg), blood lipid levels (LDL cholesterol up to 3 mmol/l, HDL cholesterol more than 1.2 mmol/l , triglycerides up to 1.7 mmol/l), control of thyroid function.

Non-drug treatment
The main task of the doctor is to convince the patient of the need to change his lifestyle. Losing weight is not always the only goal. Increasing physical activity and changes in regimen and diet also have a beneficial effect, even if it was not possible to achieve weight loss.

Nutrition

■ Principles of nutrition for type 2 diabetes: adherence to a normocaloric (if obese - hypocaloric) diet with limiting saturated fats, cholesterol and reducing the intake of easily digestible carbohydrates (no more than 1/3 of all carbohydrates).
■ Diet No. 9 - basic therapy for patients with type 2 diabetes. The main goal is to reduce body weight in obese patients. Following a diet often leads to normalization of metabolic disorders.
■ If you are overweight - a low-calorie diet (≤1800 kcal).
■ Limiting easily digestible carbohydrates (sweets, honey, sugary drinks).
■ Recommended food composition by calories (%):
✧ complex carbohydrates (pasta, cereals, potatoes, vegetables, fruits) 50–60%;
✧ saturated fats (milk, cheese, animal fat) less than 10%;
✧ polyunsaturated fats (margarine, vegetable oil) less than 10%;
✧ proteins (fish, meat, poultry, eggs, kefir, milk) less than 15%;
✧ alcohol - no more than 20 g/day (including calories);
✧ moderate consumption of sweeteners;
✧ in case of arterial hypertension, it is necessary to limit the consumption of table salt to 3 g/day.

Physical activity

Enhances the hypoglycemic effect of insulin, helps to increase the content of anti-atherogenic LDL and reduce body weight.
■ Individual selection taking into account the patient’s age, the presence of complications and concomitant diseases.
■ Walking instead of driving, and taking the stairs instead of using the elevator should be recommended.
■ One of the main conditions is regularity of physical activity (for example, walking 30 minutes daily, swimming 1 hour 3 times a week).
■ It should be remembered that intense physical activity can cause acute or delayed hypoglycemic conditions, so the exercise regime should be “worked out” with self-monitoring of glycemia; If necessary, the dose of hypoglycemic agents should be adjusted before exercise.
■ If the blood glucose concentration is more than 13–15 mmol/l, physical activity is not recommended.

Drug treatment type 2 diabetes mellitus

Hypoglycemic agents
■ If there is no effect from diet therapy and physical activity, hypoglycemic drugs are prescribed.
■ When fasting blood glucose is more than 15 mmol/l, oral hypoglycemic drugs are immediately added to diet treatment.

1. Drugs that help reduce insulin resistance (sensitizers).

This includes metformin and thiazolidinediones.

The starting dose of metformin is 500 mg at night or with dinner. Subsequently, the dose is increased by 2-3 grams in 2-3 doses.

Mechanism of action of metformin:
- suppression of GNG in the liver (reduction of glucose production by the liver), which leads to a decrease in fasting glucose levels.
-decrease in insulin resistance (increased glucose utilization by peripheral tissues, primarily muscles.)
- activation of anaerobic glycolysis and reduction of glucose absorption in the small intestine.
Metformin is the drug of choice for obese patients. Treatment with metformin in obese diabetic patients reduces the risk of cardiovascular complications and mortality rate. Metformin does not stimulate insulin secretion by pancreatic β-cells; a decrease in blood glucose concentration occurs due to inhibition of gluconeogenesis in the liver. The administration of metformin does not lead to the development of hypoglycemia and has a beneficial effect in obesity (compared to other antidiabetic drugs). Metformin monotherapy leads to a decrease in body weight of several kilograms; When the drug is combined with sulfonylurea derivatives or insulin, metformin prevents weight gain.
Among the side effects, dyspeptic symptoms are relatively common. Since metformin does not have a stimulating effect on insulin production, hypoglycemia does not develop during monotherapy with this drug, that is, its effect is designated as antihyperglycemic and not hypoglycemic.
Contraindications – pregnancy, severe cardiac, hepatic, renal and other organ failure

Thiazolidinediones (pioglitazone, rosiglitazone) are agonists of peroxisome proliferator-activated receptor gamma (PPAR-gamma). Thiazolidinediones activate the metabolism of glucose and lipids in muscle and adipose tissue, which leads to an increase in the activity of endogenous insulin, that is, the elimination of insulin resistance. The daily dose of pioglitazone is 15-30 mg/day, rosinlitazone - 4-8 mg (for 1-2 doses). The combination of thiazolidindines with metformin is very effective. Contraindication to use is increased levels of liver transaminases. In addition to hepatotoxicity, side effects include fluid retention and edema, which more often develop when drugs are combined with insulin.

2. Drugs that affect beta cells and enhance insulin secretion (secretogens).

These include sulfonylureas and amino acid derivatives, which are used primarily after meals. The main target of sulfonylurea drugs is the beta cells of the pancreatic islets. Sulfonylurea drugs bind to specific receptors on the beta cell membrane, this leads to the closure of ATP-dependent potassium channels and depolarization of cell membranes, which in turn promotes the opening of calcium channels. The ingestion of calcium leads to their degranulation and the release of insulin into the blood.

Sulfonylureas: chlorpromazide.

Amino acid derivatives: Gliclazide, initial – 40, daily – 80-320, 2 times a day; Glibenclamide; Glipizide; Gliquidone

3. Drugs that reduce the absorption of glucose in the intestine.

These include acarbose and guar gum. The mechanism of action of acarbose is a reversible blockade of alpha-glycosidases in the small intestine, as a result of which the processes of fermentation and absorption of carbohydrates slow down, and the rate of resorption and entry of glucose into the liver decreases. The initial dose of acrabose is 50 mg 3 times a day, subsequently it can be increased to 100 mg 3 times a day, the drug is taken immediately before meals or during meals. The main side effect is intestinal dyspepsia, which is associated with the entry of unabsorbed carbohydrates into the colon.

4.Biguanides.

Mechanism: utilization of glucose by muscle tissue by enhancing anaerobic glycolysis in the presence of endogenous or exogenous insulin. This includes metformin.

First, I prescribe monotherapy, most often metformin - if glycated hemoglobin is up to 7.5%.

Prescription of metformin at a dose of 850 mg 2 times a day, gradually increasing to 1000.

If glycated from 7.5 to 8.0%, then a two-component regimen (secretogen + metformin).

More than 8.0% use insulin therapy.

Other drugs and complications

■ Acetylsalicylic acid. Used for the treatment of patients with type 2 diabetes both as primary and secondary prevention of macrovascular complications. Daily dose - 100–300 mg.
■ Antihypertensive drugs. The target value for compensation of type 2 diabetes is to maintain blood pressure below 130/85 mm Hg, which helps reduce mortality from cardiovascular complications. If there is no effect from non-drug therapy (maintaining normal body weight, reducing salt intake, physical activity), drug treatment is prescribed. The drugs of choice are ACE inhibitors, which, in addition to a good prognostic effect on blood pressure, reduce the risk of development and progression of nephropathy. If they are intolerant, preference is given to angiotensin-II receptor blockers, calcium channel blockers (non-dehydropyridine series) or selective β-blockers. When combined with coronary artery disease, it is advisable to combine ACE inhibitors and adrenergic blockers.
■ Dyslipidemia. In type 2 diabetes, dyslipidemia occurs independently often. Among all indicators of the lipid spectrum, the most important is maintaining LDL cholesterol levels below 2.6 mmol/l. To achieve this indicator, a low-cholesterol diet is used (less than 200 mg of cholesterol per day) with a limitation of saturated fats (less than 1/3 of all dietary fats). If diet therapy is ineffective, statins are the drugs of choice. Statin therapy is advisable not only as a secondary, but also as a primary prevention of the development of coronary artery disease and macroangiopathies.
■ Triglycerides. Compensation for carbohydrate metabolism in many cases does not lead to normalization of triglyceride levels. For isolated hypertriglyceridemia, the drugs of choice are fibric acid derivatives (fibrates). Target triglyceride values ​​for type 2 diabetes are below 1.7 mmol/l. For combined dyslipidemia, statins are the drugs of choice.
■ Nephropathy. Nephropathy is a common complication of type 2 diabetes; at the onset of the disease, up to 25–30% of patients have microalbuminuria. Treatment of nephropathy begins at the stage of microalbuminuria; the drugs of choice are ACE inhibitors. Normalization of blood pressure in combination with the use of ACE inhibitors leads to a reduction in the progression of nephropathy. When proteinuria appears, blood pressure targets are tightened (up to 120/75 mmHg).
■ Polyneuropathy. Neuropathy is one of the main causes of the formation of leg ulcers (diabetic foot syndrome). Diagnosis of peripheral neuropathy is carried out based on the study of vibration and tactile sensitivity. Tricyclic antidepressants and carbamazepine are used in the treatment of painful forms of peripheral neuropathy.
■ Autonomic neuropathies. The goals of treatment are to relieve symptoms of orthostatic hypotension, gastroparesis, enteropathy, erectile dysfunction, and neurogenic bladder.
■ Retinopathy. Approximately 1/3 of patients with newly diagnosed type 2 diabetes have retinopathy. There is no pathogenetic treatment for diabetic retinopathy; laser photocoagulation is used to reduce the progression of proliferative diabetic retinopathy.
■ Cataract. Diabetes is associated with the rapid development of cataracts; compensation for diabetes can slow down the process of lens opacification.

Further management of the patient

■ Self-monitoring of glycemia - at the onset of the disease and during decompensation daily.
■ Glycosylated hemoglobin - once every 3 months.
■ Biochemical blood test (total protein, cholesterol, triglycerides, bilirubin, aminotransferases, urea, creatinine, potassium, sodium, calcium) - once a year.
■ General blood and urine analysis - once a year.
■ Determination of microalbuminuria - 2 times a year from the moment of diagnosis of diabetes.
■ Monitoring blood pressure - at every visit to the doctor.
■ ECG - once a year.
■ Consultation with a cardiologist - once a year.
■ Examination of the feet - at every visit to the doctor.
■ Examination by an ophthalmologist (direct ophthalmoscopy with a wide pupil) - once a year from the moment of diagnosis of DM, more often if indicated.
■ Consultation with a neurologist - once a year from the moment of diagnosis of diabetes.

Patient education

It is necessary to educate the patient according to the “School for Type 2 Diabetes Patients” program. Any chronic disease requires the patient to acquire an understanding of what he is suffering from, what he faces and what to do to prevent disability and in emergency cases. The patient must be oriented in treatment tactics and parameters of its control. He must be able to self-monitor the condition (if technically possible) and know the tactics and sequence of laboratory and physical monitoring of the disease, and try to independently prevent the development of complications of the disease. The program for patients with diabetes includes classes on general issues of diabetes, nutrition, self-control, drug treatment and prevention of complications. The program has been operating in Russia for 10 years, covers all regions and doctors know about it. Active education of patients leads to improvement of carbohydrate metabolism, reduction of body weight and lipid metabolism.
The most common way of self-monitoring, without using any instruments, is to determine blood glucose using test strips. When a drop of blood is applied to the test strip, a chemical reaction occurs, causing a color change. The color of the test strip is then compared with the color scale printed on the bottle in which the test strips are stored, and thus the blood glucose level is visually determined. However, this method is not accurate enough.
A more effective means of self-monitoring is the use of glucometers - individual devices for self-monitoring. When using glucometers, the analysis process is completely automated. The test requires a minimal amount of blood. In addition, glucometers are often equipped with a memory that allows you to record previous results, which is useful for managing diabetes. Glucometers are portable, accurate and easy to use. There are many types of glucometers available today. All types of devices have their own characteristics of use, which you must familiarize yourself with using the instructions. Strips for glucometers, as well as visual ones, are disposable, and only strips produced by the manufacturer are suitable for a glucometer from a certain company. Ideal for self-control - measuring blood sugar on an empty stomach before main meals and 2 hours after eating, before bed. Frequent measurement of glycemia is necessary when selecting a dose for insulin therapy and decompensation. When compensation is achieved and there is no bad health, less frequent self-control is possible.
Determining urine sugar is a less informative way to assess the state of the body, since it depends on the individual “renal threshold” and represents the average blood sugar level since the last urination, rather than reflecting true fluctuations in blood sugar.
Another method of self-monitoring is to determine the content of acetone in the urine. As a rule, acetone in the urine must be determined if the blood glucose level exceeds 13.0 mmol/l for a long time or the urine glucose level is 2% or higher, as well as if there is a sudden deterioration in health, if signs of diabetic ketoacidosis appear (nausea, vomiting, smell of acetone from the mouth, etc.) and when other diseases occur. The detection of acetone in the urine indicates the risk of developing a diabetic coma. In this case, you should immediately consult a doctor.

Forecast

Maintaining normal glucose levels can delay or prevent the development of complications.
The prognosis is determined by the development of vascular complications. The incidence of cardiovascular complications among patients with diabetes (9.5–55%) is significantly higher than that in the general population (1.6–4.1%). The risk of developing coronary artery disease in diabetic patients with concomitant hypertension increases 14 times over the course of 10 years of life. In patients with diabetes, the incidence of lower extremity lesions with the development of gangrene and subsequent amputation is sharply increased.

In a healthy person, the hormone insulin opens “doors” in the cell walls, allowing glucose from the bloodstream through them, which is so necessary for the body to obtain energy. In a patient with type 2 diabetes, the cells resist the effects of insulin on them. The rejection of insulin by cells does not allow glucose to penetrate into them in the required quantity.

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 needed. In diabetes, even if increased due to the body's compensatory reaction, 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. Excess weight also increases the risk of etiology of type 2 diabetes, high blood pressure and heart disease can also be causes.

The vast majority of diabetics have type 2 diabetes, mainly due to excess weight or the patient's age over forty years. A sedentary lifestyle and 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 mellitus

There is also a critical genetic component to the etiology of type 2 diabetes. The more relatives a person has 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 usually have diabetes experience increased 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 identified:

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

I.Yu.Demidova

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

The incidence of familial cases of type 2 diabetes in different ethnic groups ranges from 30 to 50%. Concordance for type 2 diabetes 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 glucokinase defect, 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 mitochondrial defect, or other genetic syndromes. For “classical” type 2 diabetes, the concept of polygenic inheritance has now been accepted.

A sedentary lifestyle and overeating lead to the development of obesity, aggravate existing IR and contribute to the development of genetic defects directly responsible for the development of type 2 diabetes.

Obesity, especially visceral (central, android, abdominal), plays an important role in the pathogenesis of IR and associated metabolic disorders, and type 2 diabetes. Thus, in contrast to subcutaneous fat cells, visceral adipocytes are characterized by reduced sensitivity to the antilipolytic action of insulin and increased sensitivity 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 effects of insulin, which promotes the re-esterification of FFA to TG. IR of skeletal muscles and their predominant utilization of FFAs at rest prevent the utilization of glucose by myocytes, which leads to hyperglycemia and compensatory hyperinsulinemia. In addition, FFAs interfere with the binding of insulin to hepatocytes, which aggravates IR at the liver level and suppresses the inhibitory effect of the hormone on hepatic gluconeogenesis (HGG). The latter circumstance causes 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 aggravates existing IR. Translocation of the glucose transporters GLUT-4 in muscle tissue is sharply reduced at rest. Muscle contractions during physical activity increase the transport of glucose into myocytes due to increased translocation of GLUT-4 to the cell membrane.

Insulin resistance, which necessarily occurs in type 2 diabetes, is a condition characterized by an insufficient biological response of cells to insulin when its concentration in the blood is sufficient. The phenomenon of IR was described in the late 30s. Himsworth and Kerr.

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

In Fig. Figure 1 shows the flow of glucose through the cell membrane in insulin-dependent tissues under normal conditions and with insulin resistance.

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

— violation of the ratio of “12+” and “12-” isoforms of the insulin receptor with a predominance of the low-affinity “12+” isoform;

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

— mutations in the insulin receptor substrate gene 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, detected in patients with type 2 diabetes;

- decreased glycogen synthetase activity.

One of the most important consequences of IR are 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 capabilities of β-cells in individuals with IR are often limited due to a genetic defect in glucokinase and/or the glucose transporter GLUT-2, which are responsible for insulin secretion in response to glucose stimulation. In Fig. Figure 2 schematically shows insulin secretion when stimulated 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 food is delayed and reduced, the concentration of proinsulin and its metabolic products is increased, and the rhythm of fluctuations in insulin secretion is disrupted. However, it is not entirely clear whether these changes are a consequence of a primary (genetic) defect of b-cells, or whether they develop secondary to the phenomenon of glucose toxicity, lipotoxicity (exposure to increased concentrations of FFAs), or due to some 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 disrupted. 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 normal weight individuals without IR. This means that in individuals with IGT, insulin secretion is no longer sufficient. Why does this decrease in insulin secretion occur?

It is possible that early in the course of impaired glucose tolerance in

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

FFA, which leads to inhibition of glycolysis by inhibiting

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

to reduce the formation of ATP, which is the most important stimulator

insulin secretion. The role of the phenomenon of glucotoxicity in development

Impaired insulin secretion in individuals with IGT is excluded, since

no hyperglycemia yet,

Glucotoxicity 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 a factor in its progression due to the existence of the phenomenon of glucose toxicity.

With prolonged hyperglycemia, a weakening of insulin secretion in response to a glucose load is observed, while the secretory response to stimulation with arginine, on the contrary, remains enhanced for a long time. All of these disorders of insulin secretion are eliminated while maintaining normal blood glucose levels, 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, glucotoxicity reduces the sensitivity of peripheral tissues to insulin, so achieving and maintaining normoglycemia will to some extent increase the sensitivity of peripheral tissues to insulin.

Thus, it is obvious that hyperglycemia is not only a marker, but also an important pathogenetic link in type 2 diabetes, disrupting 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 type 2 diabetes.

An early symptom of incipient type 2 diabetes is fasting hyperglycemia, caused by 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 hepatocyte IR is not a primary defect, but occurs secondary to the influence of hormonal and metabolic disorders, in particular, increased glucagon secretion. b-cells with prolonged chronic hyperglycemia lose the ability to respond to further increases in glycemia by decreasing glucagon production. As a result, hepatic gluconeogenesis (HNG) and glycogenolysis increase, which is one of the reasons for the relative deficiency of insulin in the portal circulation.

An additional factor causing 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 sharply stimulates the NPG 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 formation of lactate in the Cori cycle, one of the main substrates for NPH. In addition to the above, FFAs inhibit the activity of glycogen synthase.

Thus, summing up all of the above, the pathogenesis of type 2 diabetes can currently be presented in the form of the following diagram (Fig. 3).

In recent years, 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 secreted together with insulin in a molar ratio of approximately 1:100. Its content is increased in individuals with IR, IGT and hypertension. In type 2 diabetes, it is deposited in the form of amyloid in the islets of Langerhans. Amylin is involved in the regulation of carbohydrate metabolism, modulating the rate of glucose absorption from the intestine, and inhibiting insulin secretion in response to glucose stimulation.

The role of leptin in lipid metabolism disorders and the development of type 2 diabetes has received considerable attention over the past decade. Leptin, a polypeptide synthesized by adipocytes of white adipose tissue, acts on the ventrolateral nuclei of the hypothalamus, regulating eating behavior. Leptin production decreases during fasting and increases during 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 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 *NP-Y by the hypothalamus. *The latter regulates eating behavior, causing hyperphagia, weight gain, increased body fat and decreased activity of the sympathetic nervous system. In animals, administration of *NP-Y into* the ventricles of the brain causes the rapid development of obesity. Both absolute and relative leptin deficiency leads to increased formation of *NP-Y* in the hypothalamus and, as a consequence, to the development of obesity. Exogenous administration of leptin in case of its absolute deficiency reduces the content of mRNA encoding NP-Y, in parallel with a decrease in appetite and body weight. When there is a relative deficiency of leptin as a result of a mutation in 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 a loss of inhibitory control over the formation of *NP-Y,* which in turn is accompanied by neuroendocrine and autonomic disorders that play a certain role in the formation of obesity syndrome.

So, the pathogenesis of type 2 diabetes is a complex, multi-level process in which the leading role is played by *IR,* impaired insulin secretion and a chronic increase in glucose production by the liver (see Fig. 2).

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

today the links in the pathogenesis of this disease with the aim of

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

A new look at the pathogenesis of type II diabetes mellitus

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

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

Type II diabetes mellitus (non-insulin-dependent) is the most common form of diabetes mellitus (DM), which clinically manifests itself, as a rule, in middle-aged and elderly people. The number of people suffering from this type of diabetes (up to 80% of all patients with diabetes) is growing catastrophically throughout the world, becoming epidemic. About 700 thousand such patients are registered in Ukraine, and approximately the same number are being treated with an unknown diagnosis for other diseases. It is predicted that the number of patients with type II diabetes mellitus will increase to 3.5-4 million in 20 years.

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 is manifested by the formation of persistent hyperglycemia. It is believed that an increase in glucose levels in the body underlies many of the complications characteristic of this form of diabetes. That is why, when treating 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 b-cells of the pancreas, inhibiting the absorption of carbohydrates in the intestine, increasing tissue sensitivity to insulin and suppressing the processes of gluconeogenesis. An opinion has formed that the development of complications of type II diabetes is directly dependent on the quality of metabolic control throughout the day. This situation is also true in relation to complications that develop in type I diabetes - retinopathy, nephropathy, microangiopathy, neuropathy.

Complications of type II diabetes include pathological manifestations such 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 cause-and-effect relationship between hyperglycemia and these complications of diabetes. Firstly, they are not typical for insulin-dependent diabetes mellitus, and secondly, their development cannot be explained only by hyperglycemia. 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.

Advances in recent years in the study of the mechanisms of development of non-insulin-dependent diabetes 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 this pathology is characterized by a significant increase in the level of cytokines in the blood: 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 diabetes.

These cytokines play an important role in the initiation of both a nonspecific immune response and the formation of general defense mechanisms of the body. Normally, any excessive exposure causes activation of cells (mainly macrophages and dendritic cells) that produce these factors. 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 level of very low-density lipoproteins (VLDL), plasminogen activator inhibitor-1 (PAI-1) in the blood, and decreases 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 synthesis of cytokines and with simultaneous chronic exposure to a number of factors (obesity, overnutrition, 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 diabetes are considered as follows. IL-1 and TNF, as mentioned above, activate lipolysis processes in adipose tissue, which helps to increase 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 tissue of the body. In parallel, IL-1 and TNF activate the release of counter-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 diabetes development, these cytokines can stimulate the synthesis of insulin by pancreatic b-cells, thereby helping to reduce the severity of insulin resistance. Subsequently, 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 suppressed 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 TNP synthesis by the fat 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 associated development of atherosclerosis. Patients with type II diabetes mellitus are characterized by an increase in VLDL levels, which is associated with an increase in the amount of free fatty acids as their substrate. At the same time, the concentration of HDL decreases. The reason for this phenomenon is increased synthesis of amyloid A by the liver under the influence of cytokines. This substance replaces aminoprotein A1 in HDL, which leads to increased binding of lipoprotein by macrophages and accelerates their migration from the liver. There is an accumulation of so-called fatty macrophages, which have a pronounced tendency to adhere to the vascular wall. An increase in the level of VLDL promotes 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, by the liver, a hypercoagulable state is formed with the attraction of platelets, leukocytes and monocytes to the damaged areas of the endothelium with the formation of microthrombosis. This is where lipid deposition and accumulation of fatty macrophages occur. As a result, an atherosclerotic plaque is formed and the atherosclerosis characteristic of these patients is clinically manifested.

Naturally, the described mechanism is very simplified, since many other factors also take part in the damage to large vessels. For example, the ongoing activation of macrophages, platelets and endothelium leads to increased secretion of various growth factors, which play an important role in the pathogenesis of vascular complications of diabetes, which should be discussed separately. Macrophages promote lipid oxidation, 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 adhesion molecules on the endothelium. Lipid deposition stimulates the formation of chemotactic factors, such as IL-8, which promotes the penetration of mononuclear cells deep into the vessel wall.

An increase in the level of synthesis of IL-1 and TNF causes other manifestations of diabetes, 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 apparently also responsible for the typical distribution of fat deposits in these patients.

Since cytokines inhibit the formation of testosterone, patients with diabetes often experience decreased sexual function. It is possible that the depressive states of patients are directly related to the known effects 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 acceptance of the fact that in the genesis of most pathological syndromes, inadequate levels of interleukin-1 and tumor-necrotic factor play a primary role. 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 increased glucose levels lead 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, increases, the release of endothelial growth factor, stimulation of the formation of PAI-1, etc. Naturally, this leads to the aggravation of already identified metabolic disorders and 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 created for the development of typical complications for type I diabetes mellitus.

Based on the above, we can conclude that the principles of treatment of type II diabetes mellitus must be radically revised. Obviously, managing carbohydrate metabolism alone is symptomatic and far from sufficient. Treatment should be supplemented by simultaneous and as early as possible use of drugs that modulate lipid metabolism, hemostasis and the activity of the hypothalamic-pituitary-adrenal system. But the most adequate therapy for diabetes 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.

Targeting insulin resistance - a step forward in the treatment of diabetes

type 2 diabetes

Every year, a large number of studies are conducted around the world on diabetes mellitus (DM), the study of its pathogenetic features, diagnostic issues, and the search for new effective means of control and prevention of complications. Such close interest in this problem is caused by the increasing number of patients with diabetes. Every 10–15 years, their number approximately doubles, mainly due to the addition of patients with type 2 diabetes. If it was previously believed that type 2 diabetes was a disease that occurs in middle and old age, today it is increasingly diagnosed in younger people, and cases of insulin resistance are found 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 severe complications associated with metabolic disorders in diabetes. Atherosclerosis, arterial hypertension, myocardial infarction, stroke - a significant share of the causes of the development 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 increase in the incidence of diabetes and solve a number of medical and social problems.

Insulin resistance and pancreatic β-cell dysfunction are two major 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 first include the individual rate of cell division and death, neogenesis, as well as the expression of factors responsible for the synthesis of insulin. External causes may include infections, exocrine pathology of the pancreas, and others.

The well-known UKPDS study found that the majority of patients with type 2 diabetes had half their normal b-cell function at the time of diagnosis. The gradual deterioration of the response to normal insulin levels and the inability of pancreatic beta cells to produce sufficient amounts of 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 help preserve b-cell function. 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 of adipose tissue, skeletal muscle and liver.

The binding of Avandia to PPARg selectively activates gene transcription in target cells and consequently affects the expression of genes such as PERCK, GLUT, lipoprotein lipase and TNFb, which play a critical role in the metabolism of carbohydrates and fats.

At the molecular level, the drug's agonism to PPARg in the presence of insulin manifests itself as follows:

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

Enhances the expression of GLUT-4 (insulin-dependent substance - 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 the release of free fatty acids.

In general, Avandia increases glucose deposition in skeletal muscle and adipose tissue and reduces glucose output by the liver. The drug increases the sensitivity of adipocytes to insulin and their ability to take up 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 causing a decrease in insulin-stimulated glucose uptake, activating gluconeogenesis in the liver, and inhibiting glycogen synthesis in muscle. In addition, increased amounts of FFA significantly limit insulin secretion 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 into muscle cells, which has a positive effect on glycemic levels. Avandia inhibits the production of glucose by the liver, which may also be (at least in part) a consequence of reduced free fatty acids.

Through highly selective and potent PPARg agonism, Avandia reduces insulin resistance by restoring the ability of the liver, fat tissue and muscle to respond to insulin, thereby maintaining glucose control.

Preclinical data suggest that Avandia has a protective effect on pancreatic b-cell function, but it is still unclear whether the beneficial effects of the drug are due to its direct effect on these cells. It is believed that the therapeutic effect is due to a decrease in glucose and fatty acid levels, as well as hyperinsulinemia, which generally has a sparing 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 USA suffering from type 2 diabetes. In studies where Avandia was administered as adjunctive therapy to patients who failed maximal and submaximal doses of sulfonylureas or metformin, clinically significant and additive improvements in glucose control were evident. In addition, this effect was achieved without increasing any of the known side effects of sulfonylurea or metformin that are observed with monotherapy with these drugs.

As the UKPDS study showed, in 50% of patients with type 2 diabetes, monotherapy with metformin or sulfonylurea derivatives ceases to provide adequate glycemic control over three years. The clinical study program for Avandia included patients who had had type 2 diabetes mellitus for an average of 9 years. In this regard, its effect on glycemia is even more important, since the UKPDS study involved only patients with newly diagnosed diabetes, that is, the disease was at an earlier stage. In addition, the effectiveness 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 because it acts on the underlying causes of type 2 diabetes, rather than simply lowering glucose levels. The use of Avandia is indicated both as monotherapy to enhance the effectiveness of diet and physical activity, and as part of a combination treatment in case of insufficient hypoglycemic effect of maximum doses of metformin or sulfonylurea derivatives.

It should be noted that Avandia represents an extremely valuable new

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

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

What triggers diabetes mellitus

Diabetes mellitus is a heterogeneous pathology in which a complex of metabolic disorders develops. The main characteristic signs of type 2 diabetes are insulin resistance and poor beta cell function of varying degrees.

Modern scientific research has proven that many factors take part in the development of diabetes mellitus and that external, non-genetic factors play a significant role in the development of this disease.

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 level of physical activity, chronic fatigue, frequent stress;
• food – high in calories and leading to obesity;
• insulin resistance – impaired metabolic response to insulin;
• impaired insulin production and increased glucose production by the liver.

The role of individual etiological factors in the pathogenesis of diabetes

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

It was previously believed that the incidence of type 2 diabetes in identical (monozygotic) twins was 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 at 70-90%. This indicates a significant role of heredity in predisposition to type 2 diabetes.

Genetic predisposition is important in the development of prediabetes (impaired glucose tolerance). Whether a person will further develop diabetes 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 aggravate insulin resistance. This promotes the implementation of 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 occurs because visceral adipocytes, unlike adipocytes of subcutaneous adipose tissue, have reduced sensitivity to the antilipolytic action of the hormone insulin and increased sensitivity 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 respond to the slowing action of insulin, which promotes the re-esterification 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 increased blood sugar and a compensatory increase in insulin. Moreover, fatty acids prevent insulin from binding to hepatocytes, and this at the liver level aggravates insulin resistance and inhibits the inhibitory effect of the hormone on gluconeogenesis in the liver. Gluconeogenesis results in persistently 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 in muscle, fat and liver tissue. It also leads to the launch of lipolysis, hyperinsulinemia, and therefore to an increase in the concentration of fatty acids.

Low physical activity in patients with type 2 diabetes aggravates existing insulin resistance.

At rest, the transport of glucose transporter substances (GLUT-4) in myocytes is sharply reduced. Muscle contraction during physical activity increases the delivery of glucose to myocytes; this occurs 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. When studying the genetic defects that cause the presence of insulin resistance, it was found that it mainly occurs against the background of 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 changes in their structure. Pre-receptor insulin resistance is caused by a disorder of the early stages of insulin secretion and (or) pathology of the conversion of proinsulin into C-peptide and insulin. Post-receptor insulin resistance involves a defect in the activity of transducers that transmit the insulin signal within the cell, as well as those involved in protein synthesis, glycogen synthesis, and glucose transport.

The most important consequences of insulin resistance are hyperinsulinemia, hyperglycemia and dyslipoproteinemia. Hyperglycemia plays a leading role in disrupting insulin production and leads to its gradual relative deficiency. In patients with type 2 diabetes, the compensatory capabilities of pancreatic beta cells are limited due to genetic damage to glucokinase and the glucose transporter GLUT-2. These substances are responsible for the production of insulin when stimulated by glucose.

Insulin production in type 2 diabetics

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

• the initial phase of the secretory response to a load of glucose administered intravenously is slow;
• the secretory response to mixed food consumption is reduced and delayed;
• increased levels of proinsulin and its derivatives;
• the rhythm of fluctuations in insulin secretion is disordered.

Possible causes of impaired insulin production include primary genetic defects of beta cells and secondary developing disorders due to lipotoxicity and glucose toxicity. Research is underway to determine other causes of impaired insulin secretion.

When studying the production of insulin in patients with prediabetes, it was found that even before the level of fasting sugar increases and with normal levels of glycated hemoglobin, the rhythm of fluctuations in insulin production is already disrupted. This consists of a decrease in the ability of pancreatic beta cells to respond with peak insulin secretion to peak fluctuations in blood glucose concentrations throughout the day.

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

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, which means a slowdown in glycolysis. Inhibition of glycolysis leads to a decrease in the formation of ATP in beta cells, which is the main trigger for insulin secretion. The role of glucose toxicity in the defect in insulin secretion in patients with prediabetes (impaired glucose tolerance) is excluded, since hyperglycemia has not yet been observed.

Glucotoxicity is a set of bimolecular processes in which prolonged excessive concentrations of glucose in the blood lead 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 effect 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 normal blood sugar concentrations. This proves that the phenomenon of glucotoxicity plays an important role in the pathogenesis of defective insulin secretion in type 2 diabetes.

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

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 the secretion of insulin by beta cells of the pancreas and the uptake of glucose by tissues, which sets the goal of correcting carbohydrate metabolism disorders in patients with type 2 diabetes mellitus to normoglycemia levels.

High fasting sugar is an early symptom of type 2 diabetes, which is caused by increased sugar production by the liver. The severity of disturbances in insulin secretion 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 increased glucagon production. With chronic hyperglycemia, beta cells lose the ability to respond to rising blood glucose levels by reducing 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 considered to be 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 by increasing 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 excessive secretion of lactate in the Cori cycle (lactate is one of the main products for gluconeogenesis). Fatty acids also inhibit the activity of the enzyme glycogen synthase.

The role of amylin and leptin in the pathogenesis of type 2 diabetes mellitus

Recently, the substances amylin and leptin have been assigned 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 is located 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 mellitus, amylin accumulates in the islets of Langerhans in the form of amyloid. It is involved in the regulation of carbohydrate metabolism, adjusting the rate of glucose absorption from the intestines, and inhibiting the production of insulin in response to irritation with glucose.

Over the past 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 that is produced by white adipose tissue cells and acts in the hypothalamic nuclei. Namely, the ventrolateral nuclei, which are responsible for feeding 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 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 hypothalamic neuropeptide Y by the hypothalamus. This neuropeptide controls eating behavior, namely, it causes strong appetite, weight gain, accumulation of fat deposits, and inhibition of the sympathetic nervous system.

Both relative and absolute leptin deficiency leads to increased secretion of neuropeptide Y, and hence to the development of obesity. With 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 in the gene that encodes its receptor) does not affect weight in any way.

It can be assumed that absolute or relative deficiency of leptin leads to a loss of inhibitory control over the secretion of 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. Insulin resistance, impaired insulin production and chronic increased secretion of glucose by the liver play a major role in it. When selecting treatment to achieve compensation for type 2 diabetes and prevent complications, this should be taken into account.