Comprehensive treatment of type 2 diabetes. Description of type 2 diabetes mellitus: signs and prevention. Symptoms in women and men, is there a difference

Type 2 diabetes mellitus- symptoms and treatment

What is type 2 diabetes? We will analyze the causes of occurrence, diagnosis and treatment methods in the article by Dr. Khitaryan A.G., a phlebologist with 34 years of experience.

Definition of disease. Causes of the disease

Epidemic diabetes mellitus(SD) has been going on for a long time. According to the World Health Organization (WHO), in 1980 there were about 150 million people with diabetes on the planet, and in 2014 there were about 421 million. Unfortunately, the trend towards regression of morbidity over the past decades has not been observed, and today we can safely say that diabetes is one of the most common and serious diseases.

Type II diabetes mellitus- a chronic non-infectious, endocrine disease, which is manifested by profound disturbances in lipid, protein and carbohydrate metabolism associated with an absolute or relative deficiency of the hormone produced by the pancreas.

In patients with type II diabetes, the pancreas produces a sufficient amount of insulin, a hormone that regulates carbohydrate metabolism in the body. However, due to the violation of metabolic reactions in response to the action of insulin, a deficiency of this hormone occurs.

Insulin-dependent type II diabetes mellitus has a polygenic nature and is also a hereditary disease.

The cause of this pathology is a set of certain genes, and its development and symptoms are determined by concomitant risk factors, such as unbalanced diet, low physical activity, constant stressful situations, age from 40 years.

The growing obesity pandemic and type II diabetes are closely related and represent the main global health threats in society. It is these pathologies that are the reasons for the appearance of chronic diseases: coronary heart disease, hypertension, and hyperlipidemia.

If you find similar symptoms, consult your doctor. Do not self-medicate - it is dangerous for your health!

Symptoms of type 2 diabetes

Most often, the symptoms of type II diabetes are mild, so this disease can be detected thanks to the results of laboratory tests. Therefore, people at risk (obesity, high pressure, various metabolic syndromes, age from 40 years), you should undergo a routine examination to exclude or early detection of the disease.

The main symptoms of type II diabetes include:

permanent and unmotivated weakness, drowsiness;
constant thirst and dry mouth;
polyuria - frequent urination;
increased appetite (during the period of decompensation (progression and worsening) of the disease, appetite decreases sharply);
itching (in women, it often occurs in the perineum);
slow healing wounds;
blurred vision;
numbness of the limbs.

The period of decompensation of the disease is manifested by dry skin, a decrease in firmness and elasticity, and fungal infections. Due to abnormally elevated lipid levels, skin xanthomatosis (benign neoplasms) occurs.

In patients with type II diabetes, the nails are prone to brittleness, loss of color or the appearance of yellowness, and 0.1 - 0.3% of patients suffer from lipoid necrobiosis of the skin (fat deposits in the destroyed areas of the collagen layer).

In addition to the symptoms of type II diabetes itself, symptoms also make themselves felt late complications diseases: leg ulcers, decreased vision, heart attacks, strokes, vascular lesions of the legs and other pathologies.

Pathogenesis of type 2 diabetes mellitus

The main cause of type II diabetes is insulin resistance(loss of cell response to insulin), caused by a number of environmental and genetic factors, occurring against the background of β-cell dysfunction. According to research data, with insulin resistance, the density of insulin receptors in tissues decreases and GLUT-4 (GLUT4) translocation (chromosomal mutation) occurs.

Elevated blood insulin levels ( hyperinsulinemia) leads to a decrease in the number of receptors on target cells. Over time, β cells stop responding to rising glucose levels. As a result, a relative insulin deficiency is formed, in which carbohydrate tolerance is impaired.

Insulin deficiency leads to a decrease in the utilization of glucose (sugar) in tissues, an increase in the processes of splitting glycogen to glucose and the formation of sugar from non-carbohydrate components in the liver, thereby increasing glucose production and aggravating hymerglycemia- a symptom characterized by high blood sugar.

The endings of the peripheral motor nerves secrete a calcitonin-like peptide. It helps to suppress insulin secretion by activating ATP-dependent potassium channels (K +) in β-cell membranes, as well as suppressing glucose uptake by skeletal muscles.

Excessive levels of leptin, the main regulator of energy metabolism, suppress insulin secretion, leading to insulin resistance of skeletal muscles to adipose tissue.

Thus, insulin resistance includes various metabolic changes: impaired carbohydrate tolerance, obesity, arterial hypertension, dyslipoproteinemia and atherosclerosis. The main role in the pathogenesis of these disorders is played by hyperinsulinemia as a compensatory consequence of insulin resistance.

Classification and stages of development of type 2 diabetes mellitus

Currently, Russian diabetologists classify diabetes by the severity, as well as by the state of carbohydrate metabolism. However, the International Diabetes Federation (IDF) often makes changes in the goals of diabetes management and the classification of its complications. For this reason, Russian diabetologists are forced to constantly change the classification of type II diabetes adopted in Russia in terms of the severity and degree of decompensation of the disease.

There are three degrees of severity of the disease:

I degree - symptoms of complications are observed, dysfunction of some internal organs and systems. Improvement of the condition is achieved by adhering to a diet, the use of drugs and injections is prescribed.
II degree - complications of the organ of vision appear rather quickly, there is an active excretion of glucose in the urine, problems with the limbs appear. Drug therapy and diet are ineffective.
III degree - glucose and protein are excreted in the urine, renal failure develops. To this degree, the pathology is not amenable to treatment.

According to the state of carbohydrate metabolism, the following stages of type II diabetes are distinguished:

compensated - the normal blood sugar level achieved with the help of treatment, and the absence of sugar in the urine;
subcompensated - the level of glucose in the blood (up to 13.9 mmol / l) and in the urine (up to 50 g / l) is moderate, while there is no acetone in urine;
decompensated - all indicators characteristic of subcompensation are significantly increased, acetone is found in the urine.

Complications of type 2 diabetes

TO acute complications Type II diabetes mellitus includes:

Ketoacidotic coma is a dangerous condition in which there is a total intoxication of the body with ketone bodies, and metabolic acidosis (increased acidity), acute liver, renal and cardiovascular failure develops.
Hypoglycemic coma is a state of depression of consciousness that develops with a sharp decrease in blood glucose levels below the critical level.
Hyperosmolar coma - this complication develops within several days, as a result of which metabolism is disturbed, cells are dehydrated, and the level of glucose in the blood increases sharply.

Late complications of type II diabetes are:

diabetic nephropathy (kidney pathology);
retinopathy (damage to the retina of the eye that can lead to blindness);

polyneuropathy (damage to peripheral nerves, in which the limbs lose sensitivity);
diabetic foot syndrome (education on lower limbs open ulcers, purulent abscesses, necrotic (dying off) tissues).

Diagnosis of type 2 diabetes mellitus

In order to diagnose type II diabetes, it is necessary to assess the symptoms of the disease and conduct the following studies:

Determination of the level of glucose in blood plasma... Blood is taken from a finger on an empty stomach. A positive diagnosis of type II diabetes is established in the case of the presence of glucose over 7.0 mmol / L during the analysis two or more times on different days. Indicators may vary depending on physical activity and food intake.
Glycated Hemoglobin (HbAc1) Test... Unlike blood sugar levels, HbAc1 levels change slowly, so this test is a reliable method for diagnosis and subsequent control of the disease. An indicator above 6.5% indicates the presence of type II diabetes.
Urinalysis for glucose and acetone... In patients with type II diabetes, daily urine contains glucose, it is determined only if the blood glucose level is increased (from 10 mmol / l). The presence of three or four "pluses" of acetone in urine also indicates the presence of type II diabetes, while this substance is not found in the urine of a healthy person.
Blood test for glucose tolerance... It involves determining the concentration of glucose two hours after taking on an empty stomach a glass of water with glucose dissolved in it (75 g). The diagnosis of type II diabetes is confirmed if the initial glucose level (7 mmol / L or more) after drinking the solution increased to at least 11 mmol / L.

Treatment for type 2 diabetes

Treatment of type II diabetes involves the solution of the main tasks:

compensate for the lack of insulin;
correct hormonal and metabolic disorders;
implementation of therapy and prevention of complications.

To solve them, the following treatment methods are used:

diet therapy;
physical exercise;
the use of hypoglycemic drugs;
insulin therapy;
surgical intervention.

Diet therapy

The diet for type II diabetes, like a regular diet, assumes an optimal ratio of the main substances contained in foods: proteins should make up 16% of the daily diet, fats - 24%, and carbohydrates - 60%. The difference in type II diabetes diet lies in the nature of carbohydrates consumed: refined sugars are replaced by slowly digestible carbohydrates. Since this disease occurs in obese people, weight loss is the most important condition for normalizing blood glucose levels. In this regard, a caloric diet is recommended, in which the patient will lose 500 g of body weight weekly until the ideal weight is reached. However, the weekly weight loss should not exceed 2 kg, otherwise it will lead to excess loss of muscle and not adipose tissue. The number of calories required for the daily diet of patients with type II diabetes is calculated as follows: women need to multiply their ideal weight by 20 kcal, and men - by 25 kcal.

When following a diet, it is necessary to take vitamins, since during diet therapy, they are excreted in the urine excessively. Lack of vitamins in the body can be compensated for by rational use useful products such as fresh herbs, vegetables, fruits and berries. In winter and spring, it is possible to take vitamins in yeast form.

A properly selected system of physical exercises, taking into account the course of the disease, age and complications present, contributes to a significant improvement in the condition of a patient with diabetes. This method of treatment is good in that the need for insulitis practically disappears, since during physical exertion, glucose and lipids are burned without its participation.

Treatment with hypoglycemic drugs

Today, derivatives of hypoglycemic drugs are used:

sulfonylureas ( tolbutamide, glibenclamide);
biguanides, which reduce gluconeogenesis in the liver and increase the sensitivity of muscles and liver to insulin ( metformin);
thiazolidinediones (glitazones), similar in properties to biguanides ( pioglitazone, rosiglitazone);
alpha-glucosidase inhibitors, which reduce the rate of glucose absorption in the gastrointestinal tract ( acarbose);
agonists of glucagon-like peptide-1 receptors, stimulating the synthesis and secretion of insulin, reducing the production of glucose by the liver, appetite and body weight, slowing down the evacuation of the food bolus from the stomach ( exenatid, liraglutide);
inhibitors of depeptidyl peptidase-4, which also stimulate the synthesis and secretion of insulin, reduce the production of glucose by the liver, do not affect the rate of evacuation of food from the stomach and have a neutral effect on body weight ( sitagliptin, vildagliptin);
inhibitors of the sodium-glucose cotransporter type 2 (glyflozins), which reduce the reabsorption (absorption) of glucose in the kidneys, as well as body weight ( dapagliflozin,empagliflozin).

Insulin therapy

Depending on the severity of the disease and the complications that arise, the doctor prescribes insulin intake. This method of treatment is indicated in about 15-20% of cases. Indications for the use of insulin therapy are:

rapid weight loss for no apparent reason;
the occurrence of complications;
insufficient effectiveness of other antihyperglycemic drugs.

Surgery

Despite the many hypoglycemic drugs, the question of their correct dosage, as well as the patient's adherence to the chosen method of therapy, remains unresolved. This, in turn, creates difficulties in achieving long-term remission of type II diabetes. Therefore, surgical therapy of this disease - bariatric or metabolic surgery - is becoming increasingly popular in the world. IJF considers this method treatment of patients with type II diabetes is effective. Currently, more than 500,000 bariatric surgeries are performed worldwide every year. There are several types of metabolic surgery, the most common are gastric bypass and mini gastric bypass.

During bypass surgery, the stomach is transected below the esophagus so that its volume is reduced to 30 ml. Remaining most of the stomach is not removed, but drowned out, preventing food from entering it. As a result of the intersection, a small stomach is formed, to which the small intestine is then sewn, retreating 1 m from its end. Thus, food will directly enter the large intestine, while processing it with digestive juices will decrease. This, in turn, provokes irritation of the ileal L-cells, which contributes to a decrease in appetite and an increase in the growth of cells that synthesize insulin.

The main difference between mini-gastric bypass surgery and classic gastric bypass surgery is the reduction in the number of anastomoses (joints of intestinal segments). In traditional surgery, two anastomoses are made: the junction of the stomach and small intestine and the junction of different parts of the small intestine. With mini-gastric bypass surgery, there is only one anastomosis - between the stomach and the small intestine. Due to the small volume of the newly formed stomach and the rapid flow of food into small intestine the patient has a feeling of fullness even after taking small portions of food.

Other types of bariatric surgery include:

sleeve gastroplasty (otherwise it is called laparoscopic longitudinal resection of the stomach) - cutting off most of the stomach and forming a 30 ml gastric tube, which contributes to rapid saturation, and also avoids adherence to a strict diet;

gastric banding - reducing the volume of the stomach using a special ring (band) applied to the upper part of the stomach (this intervention is reversible).

Contraindications to surgical treatment- the patient has esophagitis (inflammation of the mucous membrane of the esophagus), varicose veins of the esophagus, portal hypertension, liver cirrhosis, peptic ulcer stomach or duodenal ulcer, chronic pancreatitis, pregnancy, alcoholism, severe cardiovascular diseases or mental disorders, as well as long-term use of hormonal drugs.

Forecast. Prophylaxis

Unfortunately, it is impossible to completely recover from type II diabetes. However, there are ways to improve the quality of life of patients with this disease.

Today there are a large number of "bases" where endocrinologists explain to patients what their way of life should be, how to eat right, what foods should not be consumed, what should be the daily physical activity.

A huge number of antihyperglycemic drugs have also been created, which are improved annually. In order for them to have a positive effect on the body, medications must be taken regularly.

Practice shows that compliance with all recommendations of endocrinologists improves the treatment of type II diabetes.

According to MFD, bariatric surgery is an operative method that improves the quality of life in type II diabetes.

The condition of patients with this disease can be significantly improved by carrying out gastrointestinal operations (therapy), as a result of which the level of glycohemoglobin and glucose in the blood is normalized, the need for the use of antidiabetic drugs and insulin is lost.

Bariatric surgery can lead to significant and sustained remission, as well as an improvement in the course of type II diabetes and other metabolic risk factors in obese patients. Surgical intervention within 5 years after diagnosis is most likely to result in long-term remission.

To prevent the onset of type II diabetes, the following preventive measures must be observed:

Diet- with excess body weight, it is necessary to monitor what is included in the diet: it is very useful to eat vegetables and fruits with a low glucose content, while limiting the use of foods such as bread, flour products, potatoes, fatty, spicy, smoked and sweet dishes.
Feasible physical activity- exhausting training is not necessary. The best option would be daily walking or swimming in the pool. Light exercise, if done at least five times a week, reduces the risk of type II diabetes by 50%.
Normalization of the psycho-emotional state- an integral method of preventing this disease. It is important to remember that stress can cause metabolic disorders that can lead to obesity and diabetes. Therefore, it is necessary to strengthen resistance to stress.

Type II diabetes mellitus is an insulin-dependent ailment in which tissues lose sensitivity to the hormone insulin. The prerequisite for the development of the disease is the accumulation of lipids on the surface of cell receptors. This condition results in the inability to metabolize glucose.

This pathological process becomes the cause of increased production of insulin in the pancreas. If diabetes of the first type does not provide for the administration of a hormone, then in this situation it is simply impossible to do without it.

The World Health Organization insists that this disease is equally diagnosed in all countries of the world. Until recently, diabetes mellitus was considered a problem for older people, but today the picture has changed radically.

According to medical statistics, diabetes is the third most fatal condition. This disease was second only to oncology and cardiovascular diseases. In many countries, disease control takes place at the state level.

Features of type 2 diabetes

This type of diabetes is one of the health problems that remain with a person for life. Modern science has not yet learned how to effectively get rid of this dangerous pathology. In addition, there is a fairly high probability of microangiopathy, which provokes problems with vision, as well as with the kidneys of a sick person.

If you systematically and efficiently control blood sugar, it is possible to take control of various aggressive changes in blood vessels:

fragility;
excessive permeability;
blood clots.

With proper therapy, ischemic changes, as well as cerebrovascular diseases, can be reduced several times.

The main goal of therapy is to compensate for the imbalance of carbohydrate metabolism, not only in the presence of problems with glucose, but also in case of secondary reactions from the metabolic side.

Over time, such changes become a prerequisite for a progressive decrease in the mass of beta cells, which are produced by the pancreas.

Hypoglycemia is an extremely dangerous condition in the elderly diabetic. If, in the first type of ailment, the restoration of the imbalance in insulin production will lead to prolonged control of the sugar level, then in the second type of pathology, therapy will be quite complex and lengthy.

Drug therapy

In cases where monotherapy in the form of adherence to the strictest diet does not give the intended result, it is necessary to connect special medical supplies that lower blood glucose levels. Some of the most advanced medications that only a healthcare professional can prescribe may not exclude carbohydrate intake. This makes it possible to minimize hypoglycemic conditions.

The choice of the drug will be carried out taking into account all the individual characteristics of the patient, as well as his anamnesis. Self-selection of drugs based on the recommendations of other diabetics is an extreme degree of irresponsibility!

This can cause significant damage to the patient's health or even cause death from diabetes.

The drugs that are used for treatment are contraindicated during pregnancy and lactation.

There are several generations of oral diabetes medications:

1st generation:

Tolbutamide (butamide). Take 500-3000 mg / day for 2-3 doses;
Tolazamide (tolinase). 100-1000 mg / day for 1-2 doses;
Chlorpropamide. 100-500 mg / day as a single dose.

2nd generation:

Nateglinide (glibenclamide). Take 1.25-20 mg / essence. This can be 1-2 doses;
Glipizid. At 2.5-40 mg / day for 1-2 doses.

There are equally effective alternatives for the treatment of type 2 diabetes:

Metformin. Take 500-850 mg / day (2-3 doses). This drug may be prescribed to increase the level of effectiveness or to overcome insulin resistance. It is contraindicated in case of a high likelihood of developing lactic acidosis, renal failure. In addition, Metformin should not be used after X-ray contrast agents, operations, myocardial infarction, inflammation of the pancreas, alcoholism, heart problems, and also together with tetracyclines;
Acarbose. At 25-100 mg / day (3 doses). The drug is taken at the very beginning of a meal. This makes it possible to prevent hyperglycemia developing after eating. The drug is contraindicated in renal failure, inflammatory processes in the intestines, ulcerative colitis and partial obstruction of this body.

International practice of getting rid of the second type of diabetes mellitus

There is proven evidence that controlling blood sugar can help reduce the likelihood of complications from diabetes. For this, a diabetes management tactic was created, which provides for 4 stages:

diet food low in carbohydrates;
physical activity according to the prescribed treatment regimens;
medications;
hormonal injections, but only when the need arises.

Compensation of carbohydrates must be carried out taking into account the degree of the course of the disease (chronicity, exacerbation, remission). The cyclicity of diabetes mellitus involves the use of drugs taking into account this process and possible daily circadian rhythms insulin production.

Thanks to a low-carb diet, it is possible to reduce sugar and bring it into the normal range. At the subsequent stages, regular glycemic control is performed. If the drug is not sufficient to adequately maintain glucose, then special physiotherapy exercises for diabetes may be recommended. It will help remove excess carbohydrates from the body, and will act as a kind of treatment.

In some situations, only the first levels of diabetes control may be prescribed. in the form of tablets can be shown only under the condition of an uncontrolled course of the disease, as well as an increase in glycemia. In some cases, additional insulin injections may be made. This is necessary to bring glucose back to normal levels.

Diet food for type 2 diabetes mellitus

Treatment of this pathology should begin with an adequate diet, which is always based on the following principles:

fractional meals at least 6 times a day. It is very good to eat at the same time every day;
calorie content cannot exceed 1800 kcal;
normalization of excess weight in a patient;
limiting the amount of saturated fat consumed;
reducing the consumption of table salt;
minimizing alcoholic beverages;
eating food with a high percentage of trace elements and vitamins.

If there is a deterioration in fat metabolism against the background of developed glycemia, then this becomes a prerequisite for the occurrence of blood clots in the vessels. The fibrinolytic activity of human blood and the degree of its viscosity can affect the level of platelets, as well as fibrinogen - those factors that are responsible for blood clotting.

Carbohydrates cannot be completely eliminated from the diet, because they are extremely important for saturating the cells of the body with energy. If there is a lack of it, then the strength and frequency of contractions in the heart and vascular smooth muscles may be impaired.

Physiotherapy

Against the background of type 2 diabetes mellitus, various physical activities can be successfully applied, which help to better cope with the disease, this is also a kind of treatment that goes in combination. It can be:

swimming;
walking;
a ride on the bicycle.

Healing exercises give positive result by lowering blood sugar, however, this effect is short-lived. The duration and the nature of the load itself should be selected strictly individually for each diabetic.

Physical education sets you up for a good emotional mood and makes it possible to better cope with stressful situations. It also increases the level of endorphins, the hormones responsible for pleasure, and increases the concentration of testosterone (the main male hormone).

How is the treatment carried out?

Medicine has established that glycosylated hemoglobin becomes a control marker of type 2 diabetes mellitus. The starting point is considered to be the concentration of this important substance, which will be equal to 7 percent.

If this indicator drops to 6 percent, then in this case it becomes a signal to start getting rid of the disease. In some situations, this concentration may be considered normal.

At the beginning of diabetes mellitus, it is possible to normalize the patient's condition with the help of dietary nutrition and exercise therapy. Severe weight loss makes it possible to keep glycemia under control. If this is not enough, then it is necessary to connect drugs.

Experts recommend on initial stages use metformin for treatment. This agent helps to more accurately control blood glucose. If there are no significant contraindications, then the following drugs can be connected:

biguanides. These diabetes treatments have an impressive history. In view of the likelihood of acidosis developing against the background of the available lactic acid in the blood and high glucose levels, the use of biguanides for another 20 years made it possible for patients to keep their blood sugar at an acceptable level. Over time, buformin and phenformin with their derivatives were excluded from the therapy regimen;
sulfonylurea preparations. This group of drugs is responsible for the production of insulin in the pancreas. Such a substance is extremely important for improving the absorption of glucose. Treatment of the second type of ailment with sulfonylurea preparations should be started with small doses. If the patient has increased glucose toxicity, then each time the volume of the injected substance must be produced under glucose control;
glitazones (thiazolidinediones). These drugs are in a class of oral hypoglycemic drugs. They help increase cell responsiveness. The whole mechanism of action is that the expression of multiple genes increases, which are responsible for controlling the processing of sugar and fatty acids;
glinides (prandial regulators). These drugs lower blood sugar. Their action is to stop the ATP-sensitive channels. This group of drugs includes nateglinide, as well as repaglinide;
alpha-glucosidase inhibitors can compete with carbohydrates. They perform a bunch of intestinal enzymes and take part in the breakdown of glucose. In domestic medical practice, they use medicine acarbose.

In people with type 2 diabetes, it is important to control blood sugar levels and this is where any therapy should begin. For this, each of the patients must have their own glucometer, without which treatment is complicated. Controlling the glucose concentration is extremely important in the presence of heart disease, which are combined with a too rapid frequency of its contraction and high blood pressure.

How is impaired glucose uptake treated?

Treatment to correct glucose malabsorption must be effective. All pathophysiological aspects of this disease make it possible to maintain target glycemic levels.

A medical study that was aimed at testing the effectiveness of insulin therapy in patients with type 2 diabetes mellitus showed that with high concentrations of sugar, it is not always possible to normalize it with oral medications.

When deciding on the methods of therapy, it is important to understand that the disease will have to get rid of for a long time. If we talk about combination therapy, then it can be carried out throughout the life of such a patient.

Studies have shown that diabetes only gets worse over time. An exacerbation of pathologies begins, which provide for treatment with the help of means other than those indicated above.

Type 2 diabetes is treated differently for each individual patient. If one patient, even after 10 years, does not have a lesion of the walls of blood vessels, then another can begin quite quickly.

If the disease is constantly progressing, then this should not be left without attention and control of glycosylated hemoglobin. If there is even an insignificant decrease in it, then in this case symptomatic drugs or insulin therapy should be prescribed.

First of all, it is important to note that second-degree diabetes mellitus progresses extremely slowly, so a typical patient cannot always recognize the predominance of pathology in his own body. The first signs of violations endocrine system are poorly expressed, so many simply ignore them. In the meantime, the disease continues to prevail, moreover, the pathological process is slowly but surely progressing, giving diabetes mellitus the status of a chronic disease.

The first symptoms, due to which doubts and suspicions creep in, are an irresistible feeling of thirst, frequent urination and dry mucous membranes. The patient often goes to relieve himself, and this also happens during a night's sleep, therefore disorientation in space very often progresses, and a disturbance in the work of the central nervous system occurs.

In addition, there are complaints of severe itching and weight gain. In the latter case, all diets are useless, and the patient is rapidly gaining weight, and after a couple of months they will find out from the doctor that they suffer from one of the forms of obesity. This is not surprising, since the affected organism is dominated by an increased appetite due to the high concentration of insulin in the blood.

In more advanced clinical pictures, a slightly different symptomatology predominates, which already constitutes a threat to the patient's life. These are hyperosmolar coma, angiopathy or neuropathy, where each condition entails the most irreversible health consequences. Thus, a hyperosmolar coma provokes an increase in glucose concentration, as a result of which complete or partial dehydration of the body prevails. In this clinical picture, immediate hospitalization is required, otherwise the victim's life may not be saved.

Angiopathy is accompanied by fragility of blood vessels, as a result of which not only the general blood flow is disturbed, but also serious diseases of the cardiovascular system progress. Moreover, in the case of type II diabetes mellitus, large-scale damage to the walls of large vessels first occurs, and microangiopathy progresses. But the diabetic foot is one of the most serious complications of the characteristic ailment.

Among the additional symptoms that become a problem in the patient's life, the following can be distinguished:

the progression of chronic pyelonephritis and cystitis;
a rapid drop in visual acuity;
a serious violation of the biochemistry of fluids, in particular, lens opacity;
reduced resistance to all viruses and pathogenic infections;
Long course of infectious diseases;
Weakening of immunity.

In any case, the most irreversible processes take place in the human body that turn the patient into a disabled person and make him live on pills. That is why early diagnosis and prompt treatment of second degree diabetes mellitus is so important.

The main goals of treatment for any type of diabetes mellitus include maintaining a normal lifestyle; normalization of the metabolism of carbohydrates, proteins and fats; prevention of hypoglycemic reactions; prevention of late complications (consequences) of diabetes; psychological adaptation to life with chronic disease... These goals can only be partially achieved in diabetic patients, which is due to the imperfection of modern substitution therapy... At the same time, today it is firmly established that the closer the patient's glycemia to normal levels, the less likely the development of late complications of diabetes.

Despite numerous publications devoted to the treatment of type 2 diabetes mellitus, in the vast majority of patients, compensation of carbohydrate metabolism is not achieved, although their general well-being may remain good. The diabetic does not always realize the importance of self-control and the study of glycemia is carried out from time to time. The illusion of relative well-being, based on normal well-being, has delayed the initiation of drug treatment in many patients with type 2 diabetes. In addition, the presence of morning normoglycemia does not exclude the decompensation of diabetes mellitus in such patients.

The key to the success of the treatment of patients with type 2 diabetes mellitus is education in a diabetic school. Educating patients at home on how to treat and manage their diabetes at home is essential.

Diet to treat type 2 diabetes

90% of patients with type 2 diabetes mellitus have some degree of obesity, therefore, weight loss through low-calorie nutrition and physical activity is of paramount importance. It is necessary to motivate the patient to lose weight, since even a moderate weight loss (by 5-10% of the initial) can achieve a significant decrease in glycemia, blood lipids and blood pressure... In some cases, the condition of patients improves so much that there is no need for antihyperglycemic drugs.

Treatment usually begins with dietary choices and, if possible, increases the amount of physical activity. Diet therapy is the mainstay of type 2 diabetes mellitus treatment. Diet therapy consists in prescribing a balanced diet containing 50% carbohydrates, 20% proteins and 30% fats and observing regular 5-6 meals a day - table number 9. Strict adherence to diet number 8 with fasting days for obesity and increasing physical activity can significantly reduce the need in hypoglycemic drugs.

Exercise, by decreasing insulin resistance, helps reduce hyperinsulinemia and improves carbohydrate tolerance. In addition, the lipid profile becomes less atherogenic - total plasma cholesterol and triglycerides decrease and lipoprotein cholesterol increases. high density.

A low-calorie diet can be balanced or unbalanced. A balanced low-calorie diet reduces the total calorie content of food without changing its quality composition, in contrast to an unbalanced diet low in carbohydrates and fats. The diet of patients should contain foods with high content fiber (cereals, vegetables, fruits, wholemeal bread). It is recommended to include fiber, pectin or guar-guar in the diet in the amount of 15 g / day. If it is difficult to limit fat in food, it is necessary to take orlistat, which prevents the breakdown and absorption of 30% of the fat taken and, according to some reports, reduces insulin resistance. The result from diet monotherapy can only be expected with a weight loss of 10% or more from the initial one. This can be achieved by increasing physical activity along with a low-calorie, balanced diet.

Of the sugar substitutes today, aspartame (a chemical compound of aspartic and phenylalanic amino acids), sucrasite, sladex, saccharin are widely used. A diabetic patient's diet may include acarbose, an amylase and sucrase antagonist that reduces the absorption of complex carbohydrates.

Exercise to treat type 2 diabetes

Daily exercise for type 2 diabetes is a must. This increases the absorption of glucose by the muscles, the sensitivity of peripheral tissues to insulin, improves the blood supply to organs and tissues, which leads to a decrease in hypoxia, an inevitable companion of poorly compensated diabetes at any age, especially the elderly. The amount of exercise in the elderly, hypertensive patients and those with a history of myocardial infarction should be determined by a physician. If there are no other prescriptions, you can limit yourself to a daily 30-minute walk (3 times for 10 minutes).

With the decompensation of diabetes mellitus, exercise is ineffective. With high physical exertion, hypoglycemia may develop, therefore, the doses of antihyperglycemic drugs (and especially insulin) should be reduced by 20%.

If diet and exercise fail to achieve normoglycemia, if this treatment does not normalize the disturbed metabolism, medical treatment of type 2 diabetes should be resorted to. In this case, tableted antihyperglycemic drugs, sulfonamides or biguanides are prescribed, and in case of their ineffectiveness, a combination of sulfonamides with biguanides or antihyperglycemic drugs with insulin. New groups of drugs - secretagogues (NovoNorm, Starlix) and insulin sensitizers that reduce insulin resistance (thiazolidinediones derivative - pioglitazone, Aktos). With complete depletion of residual insulin secretion, they switch to insulin monotherapy.

Medication for type 2 diabetes

More than 60% of patients with type 2 diabetes mellitus are treated with oral hypoglycemic drugs. For more than 40 years, sulfonylurea has remained the mainstay of oral glucose-lowering therapy for type 2 diabetes mellitus. The main mechanism of action of sulfonylurea drugs is to stimulate the secretion of its own insulin.

Any sulfonylurea preparation, after oral administration, binds to a specific protein on the β-cell membrane of the pancreas and stimulates insulin secretion. In addition, some sulfonylurea preparations restore (increase) the sensitivity of β-cells to glucose.

The effect is attributed to sulfonylurea drugs, which consists in increasing the sensitivity of cells of adipose, muscle, liver and some other tissues to the action of insulin, in increasing the transport of glucose in skeletal muscles. For patients with type 2 diabetes mellitus with a well-preserved function of insulin secretion, the combination of a sulfonylurea drug with a biguanide is effective.

Sulfonamides (sulfonylurea preparations) are derivatives of a urea molecule in which the nitrogen atom is replaced by various chemical groups, which determines the pharmacokinetic and pharmacodynamic differences between these drugs. But they all stimulate insulin secretion.

Sulfonamide preparations are rapidly absorbed, even when taken with food, and therefore can be taken with meals.

Sudphanilamides for the treatment of type 2 diabetes mellitus

Let's give brief description the most common sulfonamides.

Tolbutamide (Butamid, Orabet), tablets of 0.25 and 0.5 g - the least active among sulfonamides, has the shortest duration of action (6-10 hours), and therefore can be prescribed 2-3 times a day. Although this is one of the first sulfonylurea preparations, it is still used today, since it has little side effects.

Chlorpropamide (Diabenez), tablets of 0.1 and 0.25 g - has the longest duration of action (more than 24 hours), is taken once a day, in the morning. It causes many side effects, the most serious is long-term and difficult-to-eliminate hypoglycemia. Severe hyponatremia and antabuse-like reactions were also observed. Currently, chlorpropamide is rarely used.

Glibenclamide (Maninil, Betanaz, Daonil, Euglucon), 5 mg tablets are one of the most commonly used sulfonamides in Europe. It is prescribed, as a rule, 2 times a day, in the morning and in the evening. The modern pharmaceutical form is micronized maninil at 1.75 and 3.5 mg, it is better tolerated and more powerful.

Glipizid (Diabenez, Minidiab), tablets of 5 mg / tab. Like glibenclamide, this drug is 100 times more active than tolbutamide, the duration of action reaches 10 hours, usually 2 times a day.

Gliclazide (Diabeton, Predian, Glidiab, Glizid), 80 mg tablets - its pharmacokinetic parameters are somewhere between the parameters of glibenclamide and glipizide. Usually prescribed 2 times a day, now there is modified release diabetone, it is taken 1 time a day.

Glickvidone (Glurenorm), tablets of 30 and 60 mg. The drug is completely metabolized by the liver to an inactive form, therefore it can be used in chronic renal failure. Practically does not cause severe hypoglycemia, therefore it is especially indicated for elderly patients.

Modern sulfonamides of the 3rd generation include glimepiride (Amaryl), tablets of 1, 2, 3, 4 mg. It has a powerful prolonged hypoglycemic effect similar to Maninil. It is used once a day, the maximum daily dose is 6 mg.

Side effects of sulfonamides

Severe hypoglycemia occurs infrequently with sulfonamides, mainly in patients receiving chlorpropamide or glibenclamide. The risk of developing hypoglycemia is especially high in elderly patients with chronic renal failure or against the background of an acute intercurrent illness, when food intake is reduced. In the elderly, hypoglycemia is manifested mainly by mental or neurological symptoms making it difficult to recognize. In this regard, it is not recommended to prescribe long-acting sulfonamides to the elderly.

Very rarely, in the first weeks of treatment with sulfonamides, dyspepsia, cutaneous hypersensitivity or a reaction of the hematopoietic system develop.

Since alcohol suppresses gluconeogenesis in the liver, its intake can cause hypoglycemia in a patient receiving sulfonamides.

Reserpine, clonidine and non-selective β-blockers also contribute to the development of hypoglycemia, suppressing the counterinsulin regulatory mechanisms in the body and, in addition, can mask early symptoms hypoglycemia.

Reduce the effect of sulfonamides diuretics, glucocorticoids, sympathomimetics and nicotinic acid.

Biguanides (metformin) for the treatment of type 2 diabetes

Guanidine-derived biguanides increase glucose uptake by skeletal muscle. Biguanides stimulate the production of lactate in muscles and / or organs abdominal cavity and therefore, many patients receiving biguanides have elevated lactate levels. However, lactic acidosis develops only in patients with reduced elimination of biguanides and lactate or with increased production of lactate, in particular, in patients with reduced renal function (they are contraindicated with an increased level of serum creatinine), with liver disease, alcoholism, and cardiopulmonary insufficiency... Lactic acidosis was especially often observed while taking phenformin and buformin, which is why they are discontinued.

For today only metformin (Glucophage, Siofor, Diformin, Dianormet) used in clinical practice for the treatment of type 2 diabetes mellitus. Since metformin reduces appetite and does not stimulate hyperinsulinemia, its use is most justified in obese diabetes mellitus, making it easier for such patients to follow a diet and contribute to weight loss. Metformin also improves lipid metabolism, lowering the level of low density lipoproteins.

Interest in metformin is currently on the rise. This is due to the peculiarities of the mechanism of action of this drug. We can say that basically metformin increases the sensitivity of tissues to insulin, suppresses the production of glucose by the liver and, naturally, reduces fasting glycemia, slows down the absorption of glucose in the gastrointestinal tract. There are additional effects of this drug, which have a positive effect on fat metabolism, blood clotting and blood pressure.

The half-life of metformin, which is completely absorbed in the intestine and metabolized in the liver, is 1.5-3 hours, and therefore it is prescribed 2-3 times a day during or after meals. Treatment begins with minimal doses (0.25–0.5 g in the morning) in order to prevent side reactions in the form of dyspeptic phenomena, which are observed in 10% of patients, but most quickly disappear. In the future, if necessary, the dose can be increased to 0.5-0.75 g per dose, prescribing the drug 3 times a day. The maintenance dose is 0.25–0.5 g 3 times a day.

Treatment with biguanides should be canceled immediately when the patient develops acute kidney disease, liver disease or cardiopulmonary insufficiency.

Since sulfonamides mainly stimulate insulin secretion, and metformin mainly improves its action, they can complement each other's antihyperglycemic action. The combination of these drugs does not increase the risk of side effects, is not accompanied by their adverse interactions, and therefore they are successfully combined in the treatment of type 2 diabetes mellitus.

Combinations of drugs in the treatment of type 2 diabetes mellitus

The expediency of using sulfonylurea preparations is beyond doubt, because the most important link in the pathogenesis of type 2 diabetes mellitus is a β-cell secretory defect. On the other hand, insulin resistance is an almost constant sign of type 2 diabetes mellitus, which necessitates the use of metformin.

Metformin in combination with sulfonylureas- a component of effective treatment, has been intensively used for many years and allows to achieve a reduction in the dose of sulfonylurea preparations. According to the researchers, combination therapy with metformin and sulfonylureas is as effective as combination therapy with insulin and sulfonylureas.

Confirmation of the observations that combination therapy with sulfonylurea and metformin has significant advantages over monotherapy contributed to the creation of an official form of the drug containing both components (Glibomet).

To achieve the main goals of diabetes mellitus treatment, it is necessary to change the previously established stereotype of treatment of patients and switch to more aggressive tactics of therapy: early initiation of combined treatment with oral hypoglycemic drugs, in some patients practically from the moment of diagnosis.

Simplicity, effectiveness and relative cheapness explain the fact that secretogens are a good complement to metformin. The combined drug Glukovans, containing metformin and a micronized form of glibenclamide in one tablet, is the most promising representative new form antidiabetic drugs. It turned out that the creation of Glucovance clearly improves not only the patient's compliance, but also reduces total number and the intensity of side effects with the same or better efficacy.

Advantages of Glucovance over Glibomet (metformin 400 mg + glibenclamide 2.5 mg): Metformin forms a soluble matrix in which particles of micronized glibenclamide are evenly distributed. This allows glibenclamide to act faster than the non-micronized form. The rapid achievement of the peak concentration of glibenclamide allows you to take Glucovans with meals, this, in turn, reduces the frequency of gastrointestinal effects that occur when taking Glibomet. The undoubted advantage of Glucovance is the presence of 2 dosages (metformin 500 + glibenclamide 2.5, metformin 500 + glibenclamide 5), which allows you to quickly select an effective treatment.

Basal insulin addition (like Monotard NM) at an average dose of 0.2 U per 1 kg of body weight, it is recommended to start the combination therapy as a single injection at night (22.00), usually the dose is increased by 2 U every 3 days until the target glycemic values of 3.9-7.2 mmol are achieved / l. In the case of a high initial level of glycemia, it is possible to increase the dose by 4 units every 3 days.

Secondary resistance to sulfa drugs.

Despite the fact that the leading mechanism for the development of type 2 diabetes mellitus is tissue insulin resistance, insulin secretion in these patients also decreases over the years, and therefore the effectiveness of treatment with sulfonamides decreases over time: in 5-10% of patients annually and in most - after 12 –15 years of therapy. This loss of sensitivity is called secondary resistance to sulfonamides, as opposed to primary, in which they are ineffective from the very beginning of treatment.

Resistance to sulfonamides is manifested by progressive weight loss, the development of fasting hyperglycemia, post-alimentary hyperglycemia, an increase in glucosuria, and an increase in HbA1c levels.

In case of secondary resistance to sulfonamides, a combination of insulin (IPD) and sulfonamides is first prescribed. The likelihood of a positive effect of combination therapy is high when it is prescribed at the earliest stages of the development of secondary resistance, that is, when the level of fasting glycemia is between 7.5-9 mmol / L.

It is possible to use pioglitazone (Aktos), a drug that reduces insulin resistance, allows you to reduce the dose of IPD and, in some cases, cancel it. Actos is taken at 30 mg 1 time per day. It can be combined with both metformin and sulfonylureas.

But the most common combination treatment regimen is that the previously prescribed treatment with sulfonamides is supplemented with small doses (8-10 IU) of medium-acting drugs (for example, NPH or ready-made “mixes” - mixtures of short-acting and prolonged-acting drugs) 1-2 times day (8.00, 21.00). The dose is increased in steps of 2-4 units every 2-4 days. In this case, the dose of sulfonamide should be maximum.

Such treatment can be combined with a low-calorie diet (1000–1200 kcal / day) for diabetes mellitus in obese people.

If the mode of a single administration of insulin is ineffective, it is administered 2 times a day, with glycemic control at critical points: on an empty stomach and at 17.00.

Typically, the required dose of IPD is 10–20 U / day. When the need for insulin is higher, this indicates complete resistance to sulfonamides, and then insulin monotherapy is prescribed, that is, sulfa drugs are completely canceled.

The arsenal of hypoglycemic drugs used in the treatment of type 2 diabetes mellitus is quite large and continues to grow. In addition to sulfonylurea and biguanide derivatives, these include secretogens, amino acid derivatives, insulin sensitizers (thiazolidinediones), α-glucosidase inhibitors (glucobay), and insulins.

Glycemic regulators for type 2 diabetes

Based on the important role of amino acids in the process of insulin secretion by β-cells directly in the process of eating, scientists investigated the hypoglycemic activity of analogs of phenylalanine, benzoic acid, synthesized nateglinide and repaglinide (NovoNorm).

Novonorm is an oral fast-acting hypoglycemic drug. Rapidly lowers blood glucose levels by stimulating the release of insulin from the functioning β-cells of the pancreas. The mechanism of action is associated with the ability of the drug to close ATP-dependent channels in the membranes of β-cells by acting on specific receptors, which leads to cell depolarization and the opening of calcium channels. As a result, increased calcium influx induces β-cell insulin secretion.

After taking the drug, the insulinotropic response to food intake is observed within 30 minutes, which leads to a decrease in blood glucose levels. There is no increase in insulin concentration between meals. In patients with non-insulin dependent diabetes mellitus type 2, when taking the drug in doses from 0.5 to 4 mg, there is a dose-dependent decrease in blood glucose levels.

Insulin secretion stimulated by nateglinide and repaglinide is close to the physiological early phase of hormone secretion in healthy individuals after a meal, which leads to effective reduction peaks of glucose concentration in the postprandial period. They have a quick and short-term effect on insulin secretion, thereby preventing a sharp increase in blood glucose after eating. If you skip a meal, these drugs are not used.

Nateglinid (Starlix)- a phenylalanine derivative. The drug restores early insulin secretion, which leads to a decrease in postprandial blood glucose concentration and the level of glycated hemoglobin (HbA1c).

Under the influence of nateglinide taken before meals, the early (or first) phase of insulin secretion is restored. The mechanism of this phenomenon lies in the rapid and reversible interaction of the drug with the K + ATP-dependent channels of β-cells of the pancreas.

The selectivity of nateglinide in relation to K + ATP-dependent channels of β-cells of the pancreas is 300 times higher than that in relation to the channels of the heart and blood vessels.

Nateglinide, in contrast to other oral hypoglycemic agents, causes a pronounced secretion of insulin within the first 15 minutes after a meal, due to which postprandial fluctuations ("peaks") in blood glucose concentration are smoothed out. In the next 3-4 hours, the insulin level returns to its original values. This avoids postprandial hyperinsulinemia, which can lead to delayed hypoglycemia.

Starlix should be taken before meals. The time interval between taking the drug and eating should not exceed 30 minutes. When using Starlix as monotherapy, the recommended dose is 120 mg 3 times / day (before breakfast, lunch and dinner). If this dosing regimen fails to achieve the desired effect, a single dose can be increased to 180 mg.

Another prandial regulator of glycemia is acarbose (Glucobay)... Its action takes place in the upper part of the small intestine, where it reversibly blocks α-glucosidases (glucoamylase, sucrase, maltase) and prevents the enzymatic breakdown of poly- and oligosaccharides. This prevents the absorption of monosaccharides (glucose) and reduces the sharp rise in blood sugar after meals.

Inhibition of α-glucosidase by acarbose occurs according to the principle of competition for the active center of the enzyme located on the surface of the microvilli of the small intestine. Preventing the rise in glycemia after a meal, acarbose significantly reduces the level of insulin in the blood, which helps to improve the quality of metabolic compensation. This is confirmed by a decrease in the level of glycated hemoglobin (HbA1c).

The use of acarbose as the only oral antidiabetic agent is sufficient to significantly reduce metabolic disturbances in type 2 diabetes mellitus patients that cannot be compensated for by diet alone. In cases where such a tactic does not lead to the desired results, the appointment of acarbose with sulfonylureas (Glurenorm) leads to a significant improvement in metabolic parameters. This is especially important for elderly patients who are not always ready to switch to insulin therapy.

In patients with type 2 diabetes mellitus who received insulin therapy and acarbose, the daily dose of insulin decreased by an average of 10 units, while in patients receiving placebo, the dose of insulin increased by 0.7 units.

The use of acarbose significantly reduces the dose of sulfonylurea preparations. The advantage of acarbose is that it does not cause hypoglycemia in monotherapy.

Modern conditions dictate the need to create new drugs that allow not only to eliminate metabolic disorders, but also to maintain the functional activity of pancreatic cells, stimulating and activating the physiological mechanisms of regulation of insulin secretion and blood glucose. In recent years, it has been shown that, in addition to insulin and glucagon, the hormones incretins produced in the intestine in response to food intake are also involved in the regulation of glucose levels in the body. Up to 70% of postprandial insulin secretion in healthy individuals is due precisely to the effect of incretins.

Incretins in the treatment of type 2 diabetes

The main representatives of incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (G PP-1).

Food intake in digestive tract quickly stimulates the release of GIP and GLP-1. Incretins can also lower glycemic levels through non-insulin mechanisms by slowing gastric emptying and reducing food intake. In type 2 diabetes mellitus, the content of incretins and their effect are reduced, and the level of glucose in the blood is increased.

The ability of GLP-1 to induce an improvement in glycemic control parameters is of interest in the treatment of type 2 diabetes mellitus (the emergence of a class of incretinomimetics). GLP-1 has multiple effects on the endocrine pancreas, but its principal effect is to potentiate glucose-dependent insulin secretion.

Increased levels of intracellular cAMP stimulate GLP-1 receptors (rGPP-1), which leads to exocytosis of insulin granules from β-cells. The increase in cAMP levels, therefore, serves as the primary mediator of GLP-1-induced insulin secretion. GLP-1 enhances insulin gene transcription, insulin biosynthesis, and promotes β-cell proliferation through the activation of rGPP-1. GLP-1 also potentiates glucose-dependent insulin secretion via intracellular pathways. In the study by C. Orskov et al. it has been shown in vivo that GLP-1, when acting on α-cells, causes a decrease in glucagon secretion.

The improvement in glycemic parameters after GLP-1 administration may result from the restoration of normal β-cell function. In vitro studies indicate that glucose-resistant β-cells become glucose-competent after GLP-1 administration.

The term "glucose competence" is used to describe the functional state of β-cells that are sensitive to glucose and secreting insulin. GLP-1 has an additional antihyperglycemic effect not related to the effect on the pancreas and stomach. In the liver, GLP-1 inhibits glucose production and promotes glucose uptake by adipose and muscle tissue, but these effects are secondary to the regulation of insulin and glucagon secretion.

An increase in the mass of β-cells and a decrease in their apoptosis is a valuable quality of GLP-1 and is of particular interest for the treatment of type 2 diabetes mellitus, since the main pathophysiological mechanism this disease is precisely the progressive β-cell dysfunction. The incretin mimetics used in the treatment of type 2 diabetes mellitus include 2 classes of drugs: GLP-1 agonists (exenatide, liraglutide) and inhibitors of dipeptidyl peptidase-4 (DPP-4), which destroys GLP-1 (sitagliptin, vildagliptin).

Exenatid (Byetta) isolated from the saliva of the giant lizard Gila monster. The amino acid sequence of Exenatide is 50% identical to human GLP-1. With the subcutaneous administration of Exenatide, its peak plasma concentration occurs after 2-3 hours, and the half-life is 2-6 hours. This allows for therapy with Exenatide in the form of 2 subcutaneous injections a day before breakfast and dinner. Long-acting exenatide - Exenatide LAR, administered once a week, has been created, but has not yet been registered in Russia.

Liraglutide is a new drug, an analogue of human GLP-1, which is 97% similar in structure to human. Liraglutide maintains a stable concentration of GLP-1 for 24 hours when administered once a day.

DPP-4 inhibitors for the treatment of type 2 diabetes mellitus

The GLP-1 drugs developed to date do not have oral forms and require mandatory subcutaneous administration. Drugs from the group of DPP-4 inhibitors are devoid of this drawback. By suppressing the action of this enzyme, DPP-4 inhibitors increase the level and lifespan of endogenous GIP and GLP-1, contributing to the enhancement of their physiological insulinotropic action. The drugs are available in tablet form, usually prescribed once a day, which significantly increases the adherence of patients to the therapy. DPP-4 is a membrane-binding serine protease from the group of prolyl oligopeptidases; short peptides such as GIP and GLP-1 serve as the main substrate for it. The enzymatic activity of DPP-4 towards incretins, especially GLP-1, suggests the possibility of using DPP-4 inhibitors in the treatment of patients with type 2 diabetes mellitus.

The peculiarity of this approach to treatment is the increase in the duration of action of endogenous incretins (GLP-1), i.e., the mobilization of the body's own reserves to combat hyperglycemia.

DPP-4 inhibitors include sitagliptin (Januvia) and vildagliptin (Galvus) recommended by the FDA (USA) and the European Union for the treatment of type 2 diabetes mellitus both as monotherapy and in combination with metformin or thiazolidinediones.

The most promising is the combination of DPP-4 inhibitors and metformin, which makes it possible to influence all the main pathogenetic mechanisms of type 2 diabetes mellitus - insulin resistance, β-cell secretory response and glucose hyperproduction by the liver.

The drug GalvusMet was created (50 mg vildagliptin + metformin 500, 850 or 100 mg), which was registered in 2009.

Insulin therapy for type 2 diabetes mellitus.

Despite the definition of type 2 diabetes mellitus as "non-insulin dependent", a large number of patients with this type of diabetes eventually develop absolute insulin deficiency, which requires the administration of insulin (insulin-dependent diabetes mellitus).

Insulin treatment in the form of monotherapy is indicated, first of all, in primary resistance to sulfonamides, when diet and sulfonamide treatment does not lead to optimal glycemic levels within 4 weeks, as well as in secondary resistance to sulfonamides against the background of depletion of endogenous insulin reserves, when it is necessary to compensate exchange, the dose of insulin prescribed in combination with sulfonamides is high (more than 20 U / day). The principles of insulin treatment for insulin-dependent diabetes mellitus and type 1 diabetes mellitus are practically the same.

According to the American Diabetes Association, after 15 years, most people with type 2 diabetes require insulin. However, a direct indication for monoinsulin therapy in type 2 diabetes mellitus is a progressive decrease in insulin secretion by β-cells of the pancreas. Experience shows that approximately 40% of type 2 diabetics require insulin therapy, but in fact this percentage is much lower, more often due to patient opposition. In the remaining 60% of patients who are not indicated for monoinsulin therapy, unfortunately, treatment with sulfonylurea drugs also does not lead to compensation for diabetes mellitus.

If even during daylight hours it is possible to reduce glycemia, then almost all of them retain morning hyperglycemia, which is caused by the nighttime production of glucose by the liver. The use of insulin in this group of patients leads to an increase in body weight, which aggravates insulin resistance and increases the need for exogenous insulin, in addition, one should take into account the inconvenience caused to the patient by frequent dosing of insulin and several injections per day. Excess insulin in the body also causes concern for endocrinologists, because it is associated with the development and progression of atherosclerosis, arterial hypertension.

According to WHO experts, insulin therapy for type 2 diabetes should be started not too early and not too late. There are at least 2 ways of limiting insulin doses in patients not compensated by sulfonylurea drugs: a combination of a sulfonylurea drug with prolonged-acting insulin (especially at night) and a combination of a sulfonylurea drug with metformin.

Combination therapy with sulfonylureas and insulin has significant advantages and is based on complementary mechanisms of action. High blood glucose has a toxic effect on β-cells, and therefore decreases insulin secretion, and administration of insulin by lowering glycemia can restore the pancreatic response to sulfonylurea. Insulin suppresses the production of glucose in the liver at night, which leads to a decrease in fasting glucose levels, and sulfonylurea causes an increase in insulin secretion after meals, controlling the level of glycemia during the day.

In a number of studies, a comparison was made between 2 groups of patients with type 2 diabetes mellitus, of which 1 group received only insulin therapy, and the other - combined therapy with insulin at night with sulfonylurea. It turned out that after 3 and 6 months the indicators of glycemia, glycated hemoglobin significantly decreased in both groups, but the average daily dose of insulin in the group of patients receiving combined treatment was 14 U, and in the group of monoinsulin therapy - 57 U per day.

Average daily dose extended insulin before bedtime to suppress nocturnal hepatic glucose production is usually 0.16 U / kg / day. This combination showed an improvement in glycemic parameters, a significant decrease in the daily dose of insulin and, accordingly, a decrease in insulinemia. Patients noted the convenience of such treatment and expressed a desire to more closely follow the prescribed regimen.

Insulin monotherapy for type 2 diabetes mellitus, that is, not combined with sulfonamides, is necessarily prescribed for severe metabolic decompensation that developed during treatment with sulfonamides, as well as for painful form of peripheral neuropathy, amyotrophy or diabetic foot, gangrene (therapy only with ICD or "bolus basal").

Each patient should strive to achieve good compensation for diabetes from the first days of the disease, which is facilitated by their education in the "schools of the patient with diabetes." And where such schools are not organized, patients should be provided with at least special educational materials and diaries of a patient with diabetes. Self-directed and effective treatment also involves the provision of all patients with diabetes with portable means of rapid testing of glycemia, glucosuria and ketonuria at home, as well as ampoules with glucagon to eliminate severe hypoglycemia (a set of hypokit).

M. I. Balabolkin, V. M. Kreminskaya, E. M. Klebanova
Department of Endocrinology and Diabetology FPPO MMA named after I.M. Sechenov, Moscow

Type 2 diabetes mellitus (DM) is a heterogeneous disease, the development of which is caused by the presence of insulin resistance and impaired insulin secretion by b-cells of the islets of the pancreas. It becomes clear that the therapy of type 2 diabetes cannot be as unified as is the case with type 1 diabetes.

The goal of type 2 diabetes treatment is to achieve long-term diabetes compensation, i.e. indicators of glucose in blood plasma, which are almost identical, observed in a healthy person throughout the day. However, the qualitative and quantitative indicators of diabetes compensation have been repeatedly revised based on ongoing studies that establish the dependence of the development of late vascular complications diabetes from the state of carbohydrate metabolism. The dynamics of quantitative indicators of SD compensation is presented in table. one.

Currently, no one doubts that strict and long-term compensation of carbohydrate metabolism reduces the incidence of diabetes complications. This is convincingly shown by the results of the studies DCCT (1993) and UKPDS (1998). Maintaining glycemia close to normal values during the observation period (about 10 years) made it possible to carry out primary prevention of retinopathy in patients with type 1 diabetes by 76%; secondary prevention of retinopathy - by 54%; prevention of neuropathy - by 60%; to achieve the disappearance of microalbuminuria - by 39% and albuminuria - by 54%. The same effects can be achieved in type 2 diabetes, since the mechanisms underlying the development of complications are likely to be the same. Thus, it was found that intensive glucose-lowering therapy reduces the risk of myocardial infarction by 16%. Therefore, as before, the main task of treating diabetes is to achieve its compensation over a long period of time, which is fraught with great difficulties. This is mainly due to the fact that the treatment of diabetes is usually prescribed not from the moment of a violation of carbohydrate metabolism, detected only by carrying out various stress tests (glucose tolerance test, etc.), but only when pronounced clinical signs of diabetes appear, which, in turn, indicate the development vascular and other changes in tissues and organs.

Table 2.
Criteria for compensation of type 2 diabetes mellitus

Indicators	Low risk	Risk of arterial damage	Risk of microangiopathy

Venous blood plasma Fasting / before meals


Capillary blood glucose (self-control)
On an empty stomach / before meals


Postprandial glucose (peak)

Table 3.
Criteria for the state of lipid metabolism in patients with type 2 diabetes mellitus

Thus, the analysis of the clinical manifestations of diabetes detected during its manifestation in adults shows a high frequency of the presence of late vascular complications in them, the development of which occurs with a duration of carbohydrate metabolism disorders of 5-7 years. Our study of the frequency of vascular complications in type 2 diabetes shows that 44% of patients with newly diagnosed diabetes have one or two (retinopathy, nephropathy, macroangiopathy, etc.) vascular complications of diabetes.

The main role in the pathogenesis of vascular complications of diabetes belongs to hyperglycemia, and in type 2 diabetes and lipid metabolism disorders. European Bureau of the International Federation of Diabetologists and WHO European Bureau in 1998. proposed criteria for the compensation of metabolism in patients with type 2 diabetes, which are presented in table. 2.

In type 2 diabetes, disorders of carbohydrate metabolism are combined with pronounced changes lipid metabolism. In this regard, when considering the compensation of metabolic processes, one should also take into account the indicators of the state of lipid metabolism, which, to one degree or another, correlate with the risk of developing vascular complications of diabetes (Table 3).

The adequacy of diabetes therapy remains the most pressing issue, since it has been established that hyperglycemia is the starting point of many pathogenetic mechanisms that contribute to the development of vascular complications.

Strict diabetes compensation, i.e. by maintaining normal (or close to normal) blood glucose concentration for a long time, it is possible to delay or delay the onset of late complications of diabetes.

Treatment of type 2 diabetes

Treatment of type 2 diabetes is complex, and its components are: diet; dosed exercise stress; patient education and diabetes self-management; drug therapy (oral hypoglycemic drugs as monotherapy, combination therapy with oral drugs - drugs with different mechanisms of action, combination therapy of oral hypoglycemic drugs with insulin or the use of only insulin therapy); prevention and treatment of late complications of diabetes.

Diet with type 2 diabetes, it must meet the following requirements: a) be physiological in terms of the composition of foods (about 60% of the total calorie content of food should be carbohydrates, 24% - fats and 16% - proteins); b) the energy value food should be subcaloric (daily calorie content is about 1600-1800 kcal); c) 4-5 meals a day; d) exclude easily digestible carbohydrates from the diet and replace them with sweeteners or sweeteners; e) food must contain a sufficient amount of fiber or fiber (at least 25-30 g per day); f) of the total amount of fats, about 40-50% should be vegetable fats (1/3 of the total fat should be saturated fats; 1/3 - semi-unsaturated and 1/3 - unsaturated fats).

Multiple (4-5 times) food intake during the day allows you to more adequately modulate the relationship between the level of insulin and blood glucose, approaching those indicators that take place in a healthy person throughout the day.

Physical activity and physiotherapy exercises are an obligatory component of therapy for patients with type 2 diabetes. The volume of physical activity should be determined taking into account the patient's age, the state of the cardiovascular system and compensation of carbohydrate metabolism. They have a positive effect on the course of diabetes and help maintain a stable compensation for carbohydrate metabolism with a noticeable decrease in excess body weight. Regular physical education, regardless of its volume, contributes to the normalization of lipid metabolism, improves microcirculation, activates fibrinolysis, normalizes the increased secretion of catecholamines in response to a stressful situation, which ultimately prevents the development of vascular complications (angiopathy). In diabetic patients who regularly engage in physical education, stabilization and even regression of vascular complications of diabetes were noted.

The task patient education Type 2 diabetes mellitus is their motivation to change the lifestyle and habits that accompanied the patient throughout his life until the development of diabetes. This applies primarily to the diet (intake of almost 50% of the daily caloric intake of food falls on the afternoon or dinner), sleep and rest, to reduce physical inactivity due to regular physical activity, to quit smoking and take excessive doses of alcohol and fulfill all those activities that are components of a healthy lifestyle. Self-control of diabetes and the achievement of its compensation will contribute to the delay in the development of vascular complications of diabetes.

Drug therapy

Medication therapy for patients with type 2 diabetes includes: a) the use of various drugs that reduce the absorption of carbohydrates in the gastrointestinal tract (acarbose, etc.); b) biguanides (metformin); c) glitazones or insulin sensitizers (pioglitazone); d) the use of drugs that stimulate the secretion of insulin: sulfonylurea drugs of the second generation: glibenclamide, glipizide, gliclazide, glyvidone and sulfonylurea drugs of the third generation (glimepiride), as well as drugs derived from amino acids, -repaglinide and nateglinide, which are regulators of postprandial hyperglyremic stimulants short-acting insulin. In cases where diabetes compensation cannot be achieved with the help of oral hypoglycemic drugs (in type 2 diabetes patients with a pronounced defect in b-cells of the islets of the pancreas), it is recommended to use combination therapy (oral hypoglycemic therapy + insulin therapy, more often with drugs of average duration of action on night or 2 times a day).

Sulfonylureas represent the main group of drugs used to treat type 2 diabetes. These drugs belong to insulin secretogens, and their main glucose-lowering effect is associated with the stimulation of the formation and release of insulin from the islets of the pancreas. In recent years, the mechanism of action of sulfonylurea preparations on the stimulation of insulin secretion by b-cells of the pancreas has been fully deciphered. These drugs bind to the corresponding receptors localized on the membranes of b-cells, change the activity of K-ATPase, promote the closure of potassium channels (KATP-dependent channels) and increase the ratio of ATP / ADP levels in the cytoplasm, which leads to membrane depolarization. This, in turn, promotes the opening of voltage-dependent Ca2 + channels, an increase in the level of cytosolic calcium and stimulation of Ca2 + -dependent exocytosis of secretory granules, which results in the release of the contents of the secretory granule into the intercellular fluid and blood. The last step of insulin secretion is under the control of calcium / calmodulin-dependent protein kinase II. Thus, the target of sulfonylurea drugs are ATP-sensitive potassium channels, which consist of a sulfonylurea receptor [a 140-kDa protein (SUR)] and a specific protein (KIR6.2).

However, all second-generation sulfonylurea derivatives have certain disadvantages of greater or lesser severity, which do not allow in all cases to achieve stable diabetes compensation and normalization of carbohydrate metabolism indicators both for a long time and throughout the day. The latter is due to the fact that the peak of the action of any sulfonylurea drug and the increase in postabsorption hyperglycemia do not coincide in time. This leads, on the one hand, to an insufficient decrease in blood glucose levels for a long time, and on the other, to the development of hypoglycemia of varying severity in the hours following a meal, especially in the case of an insufficient amount or skipping a meal. Episodes of hypoglycemia are more common in elderly patients as a result of a violation of the scheme for the use of hypoglycemic drugs due to memory impairment. For example, when taking glibenclamide 2-3 times, patients often forget whether they took the drug in the morning. To compensate for the possible lack of taking the drug before breakfast, the patient takes a double dose before dinner, which leads to the development of hypoglycemia at night.

The study of the molecular mechanisms of action of sulfonylurea drugs made it possible to obtain data that shed light on the processes of interaction of various stimulators of insulin secretion and showed that insulin secretogens, despite the identical final effect manifested in increased secretion and release of insulin from b-cells, carry out this action through involvement in the corresponding process of various protein and signaling molecules.

ATP-sensitive potassium channels are the primary structures that interact with various insulin secretogens. ATP-sensitive potassium channels are a complex that includes a sulfonylurea receptor 1 [a protein with a molecular weight of 140,000 (SUR1) and a specific protein - the so-called internal purifier of potassium channels or rectifying subunit KIR6.2. The gene encoding the SUR1 receptor is localized on chromosome 11p15.1 and belongs to the family of ATP-binding cassette proteins (ABC proteins), which has 17 transmembrane domains (TMD), in which there are two nucleotide-binding sites - NBF-1 and NBF-2, specifically complexed with Mg2 + ADP / ATP. ATP-sensitive channels are like two proteins, SUR1 and KIR6.2, which are coexpressed together. The KIR6.2 locus is located within the SUR1 gene, i.e. on the same 11p15.1 chromosome.

Thus, ATP-sensitive potassium channels are "assembled-constructed" from two different subunits: the sulfonylurea receptor, which belongs to the family of ATP-binding cassettes, and the potassium channel subunits (KIR6x), forming pores and a regulatory subunit. Three sulfonylurea receptor isoforms have been cloned: SUR1 - high-affinity receptor and SUR2, SUR2B - low-affinity receptors. Structurally, potassium channels in different tissues are not the same in terms of their constituent subunits. Thus, in b-cells of the islets of the pancreas and glucose-sensitive neurons of the hypothalamus, they consist of SUR1 / KIR6.2; in the heart muscle - from SUR2A / KIR6.2 and in vascular smooth muscle cells - from SUR2B / KIR6.1 (or KIR6.2). It was shown that the ability of various drugs (glibenclamide, glipizide, tolbutamide and meglitinide) to inhibit potassium channels (SUR1 / KIR6.2 and SUR2B / KIR6.2) was 3-6 times higher than their affinity for complexing with these receptors. The closure of the potassium channel requires the binding of one of the four sulfonylurea binding sites on the “channel complex”, which is represented by the octometric structure (SUR / KIR6x) 4.

The key to understanding the mechanism of action of various sulfonylurea drugs was studies in which it was shown that the latter are combined with certain areas of TMD. Thus, glibenclamide is complexed with site 1-5 TMD, and tolbutamide - with 12-17 TMD, which indicates the modular structural and functional organization of ATP-sensitive potassium channels. As a result of conformational changes, glibenclamide disrupts the interaction between NBF 1 and SUR1 2 at the sites TMD 12-17 and especially TMD 1-5. This, in turn, causes the displacement of the TMD2KIR6.2 complex, which is in direct contact with TMD 1-5 SUR1, to induce the state of "closed potassium channels". This mechanism requires the aminoterminal end of KIR6.2 to be intact. Thus, the binding of sulfonylurea to SUR1 certainly induces a latent decrease in the required bond strength between SUR1 and KIR6.2, which is required to keep KIR6.2 at least partially open.

The opening and closing of ATP-sensitive potassium channels, and, consequently, the initiation of insulin secretion and its inhibition is provided by the complexation of ATP with various subunits of potassium channels. Binding of ATP to the carboxyterminal domain of KIR6.2 stabilizes the dissociation of SUR1 and KIR6.2 caused by glibenclamide and promotes the closure of potassium channels. The complexation of ATP with NBF-1 and Mg2 + ADP with NBF-2 on SUR1 causes the opening of potassium channels.

Despite the fact that glibenclamide and glimepiride have a stimulating effect on insulin secretion by closing ATP-sensitive potassium channels, the mechanism of this effect has certain differences. It was found that for glimepiride the association rate constants are 2.2-3 times, and the dissociation rates are 8-10 times higher than for glibenclamide. These data indicate that the affinity of glimepiride for the sulfonylurea receptor is 2-3 times lower than that of glibenclamide. In addition, glibenclamide complexed with a receptor polypeptide having a molecular weight of 140 kDa, while glimepiride with a polypeptide of the same receptor but having a molecular weight of 65 kDa, which is designated SURX. Additional studies have shown that, in addition to the main complexation with the 140 kDa polypeptide, glibenclamide also specifically complexed with proteins with molecular weights of 40 and 65 kDa, which made it possible to suggest that glibenclamide can also complex with the SURX protein, although the affinity for such complexation it is much lower than that of glimepiride. All of the above suggests that the target proteins of the sulfonylurea receptor for glibenclamide and glimepiride are different: for glibenclamide - SUR1, for glimepiride - SURX. Both proteins interact with each other and, through KIR6.2, control the opening and closing of potassium channels, and, consequently, the processes of insulin synthesis and release in the b-cell of the pancreas.

Since the use of sulfonylurea drugs for the treatment of type 2 diabetes, discussions about the extra-pancreatic (peripheral) effect of sulfonylureas have continued. Research in this direction has been carried out in the laboratory headed by G. Muller for many years. Studying in vitro and in vivo the effect of glimepiride, glipizide, glibenclamide and gliclazide on the maximum decrease in blood glucose levels and a minimum increase in insulin secretion within 36 hours after taking these drugs, it was found that glimepiride at a dose of 90 μg / kg caused the maximum decrease in glucose in the blood with minimal insulin secretion; glipizide at a dose of 180 μg / kg had the lowest glucose-lowering activity and caused the maximum increase in insulin secretion; glibenclamide at a dose of 90 μg / kg and gliclazide at a dose of 1.8 mg / kg occupied an intermediate position between the two extreme values. The curves of the dynamics of the concentration of insulin and glucose in the blood with the use of these sulfonylurea preparations were almost identical. However, when determining the coefficient (the average increase in plasma insulin levels to the average decrease in blood glucose), these indicators were not the same (glimepiride - 0.03; gliclazide - 0.07; glipizide - 0.11 and glibenclamide - 0.16). This difference was a consequence of the lower secretion of insulin: in glimepiride, the average level of insulin in plasma is 0.6 μU / ml, in gliclazide - 1.3; in glipizide - 1.6 and glibenclamide - 3.3 μU / ml (G. Muller, 2000). The least stimulating effect of glimepiride on insulin secretion provides a lower risk of hypoglycemia.

The results of these studies show that sulfonylureas have a peripheral effect to one degree or another, but this effect is more pronounced with glimepiride. The peripheral effect of glimepiride is due to the activation of GLUT-4 (to a lesser extent GLUT-2) translocation and an increase in the synthesis of fat and glycogen in fat and muscle tissue respectively. In the plasma membrane of adipocytes under the influence of glimepiride, the amount of GLUT-4 is 3-3.5 times higher, and insulin is 7-8 times higher. In addition, glimepiride causes the dephosphorylation of GLUT-4, which is an obligatory condition for the stimulation of key enzymes of lipogenesis (glycerol-3-phosphatacyltransferase) and glycogenesis (glycogen synthetase). Glimepiride, like glibenclamide, increases the activity coefficient of glycogen synthetase to 45-50% of the maximum effect of insulin. Simultaneously, the activity of glycerol-3-phosphate acyltransferase increases to 35-40% of the maximum effect of insulin. Glimepiride inhibits protein kinase A activity and lipolysis by activating cAMP-specific phosphodiesterase.

The most effective drug from the group of sulfonylureas is glibenclamide, which has been introduced into clinical practice in 1969, the biological half-life is 5 hours, and the duration of hypoglycemic action - up to 24 hours. The drug metabolism occurs mainly in the liver by conversion into two inactive metabolites, one of which is excreted in the urine, and the second is excreted through the gastrointestinal tract. The daily dose is 1.25-20 mg (the maximum daily dose is 20-25 mg), which is prescribed in 2, less often in 3 doses 30-60 minutes before meals. Glibenclamide has the most pronounced antihyperglycemic effect among the entire group of sulfonylureas, and in this regard, it is rightfully considered the "gold standard". On the domestic market, glibenclamide is presented in tablets of 5; 3.5; and 1.75 mg. Moreover, the last two dosage forms represent micronized form, which allows at a lower dose of the drug to maintain its therapeutic concentration in the blood, i.e. at a lower dose of the drug, it is possible to achieve a higher efficiency of its action. If the bioavailability of glibenclamide in 5 mg tablets is 29-69%, then its micronized forms are 100%. Glibenclamide (5 mg) is recommended to be taken 30-40 minutes before meals, and its micronized form - 7-8 minutes. The maximum action of micronized glibenclamide almost completely coincides with postabsorption hyperglycemia, therefore, in patients receiving micronized forms of the drug, hypoglycemic conditions are much less often observed, and if they develop, they proceed in a mild form.

Glipizides has been used for the treatment of type 2 diabetes since 1971 and, in terms of the strength of the hypoglycemic effect, almost corresponds to glibenclamide. It is rapidly and completely absorbed from the gastrointestinal tract. The biological half-life in plasma is 2-4 hours, the hypoglycemic effect lasts 6-12 hours, and its retard form has a duration of 24 hours.

At the same time, dosage forms of known drugs (gliclazide and glipizide) with prolonged action have been obtained. Prolongation of the action of these drugs is due to the use of technologies that slow down the absorption of the drug from the intestine.

Gliclazide proposed as a hypoglycemic drug in 1970. Gliclazide is also a second generation drug, its daily dose is 30–120 mg (available in 30 mg tablets). Our studies have shown that in patients treated with gliclazide, there was a significant decrease in platelet aggregation, a significant increase in the relative disaggregation index, an increase in heparin and fibrinolytic activity, an increase in heparin tolerance, which allowed us to speak of the normalizing effect of gliclazide on the functional state of platelets. A significant tendency towards an improvement in the aggregation function of erythrocytes, as well as a decrease in blood viscosity at low shear stresses, was noted. Plasma coagulation factors of blood coagulation, fibrinolysis, indicators of protein and lipid metabolism also tended to normalize. It stabilizes the course of microangiopathy and even causes a reverse development in some cases.

Glickvidone is also a sulfonylurea derivative, and it is also referred to as second generation drugs. However, like gliclazide, according to its characteristics, it does not fully possess all the characteristics that apply to this group. The drug is available in 30 mg tablets, and the daily dose is 30-120 mg. The difference between glycidone and drugs in this group is that 95% of the drug taken orally is excreted through the gastrointestinal tract and only 5% through the kidneys, while almost 100% of chlorpropamide and 50% of glibenclamide are excreted in the urine. The sugar-lowering effect of glycvidone is weaker in comparison with the listed drugs.

In addition, to the great satisfaction of endocrinologists in the second half of the 90s, glimepiride was proposed for the treatment of type 2 diabetes. This is the first sulfonylurea drug with a prolonged action and a low therapeutic dose (1-4 mg per day) compared to other sulfonylureas. These differences allowed glimepiride to be attributed to the III generation of sulfonylurea preparations.

Glimepiride - the first sulfonylurea preparation with a prolonged action and a low therapeutic dose (1-4 mg per day) in comparison with other sulfonylurea preparations. These differences made it possible to refer it to the third generation (generation) of sulfonylurea preparations. The half-life of glimepiride is longer (more than 5 hours) than that of other drugs in this group, which ensures its therapeutic efficacy during the day. The drug is prescribed once a day at a dose of 1–4 mg, the maximum recommended dose is 6 mg. Glimepiride is completely metabolized in the liver to metabolically inactive products.

For many years, various pharmaceutical companies have been conducting research to find new oral hypoglycemic drugs. One of these developments is the synthesis of a new oral hypoglycemic substance - repaglinide , which is a derivative of benzoic acid. Repaglinide structurally refers to meglitinide, which contains a non-sulfonylurea specific part of the glibenclamide molecule and, like sulfonylureas, stimulates insulin secretion by the mechanism described for sulfonylureas.

Biguanides. The second group of oral glucose-lowering drugs includes biguanides, which are represented by phenethyl biguanide (phenformin), N, N-dimethyl biguanide (metformin) and L-butyl biguanide (buformin).

The difference in the chemical structure of these drugs has little effect on their pharmacodynamic effect, causing only a slight difference in the manifestation of the hypoglycemic activity of each of them. but metformin is not metabolized in the body and is excreted by the kidneys unchanged, while phenformin is excreted only 50% unchanged, and the rest is metabolized in the liver. These drugs do not alter the secretion of insulin and have no effect in the absence of it. Biguanides in the presence of insulin increase the peripheral utilization of glucose, decrease gluconeogenesis, increase the utilization of glucose by the intestine, which is manifested by a decrease in the level of glucose in the blood flowing from the intestine; and also reduce the increased content of insulin in the blood serum in patients with obesity and type 2 diabetes. Their long-term use has a positive effect on lipid metabolism (lowering cholesterol, triglycerides). Biguanides increase the amount of GLUT-4, which is manifested in the improvement of glucose transport across the cell membrane. It is this effect that explains their potentiating effect on the action of insulin. The site of action of biguanides is probably also the mitochondrial membrane. By inhibiting gluconeogenesis, biguanides increase the content of lactate, pyruvate, alanine, i.e. substances that are precursors of glucose in the process of gluconeogenesis. Due to the fact that under the action of biguanides, the amount of increasing lactate exceeds the formation of pyruvate, this may be the basis for the development of lactic acidosis (lactic acidosis).

In Russia, as in all countries of the world, from the group of biguanides, only metformin is used. The half-life of metformin is 1.5-3 hours. The drug is available in tablets of 0.5 and 0.85 g. Therapeutic doses are 1-2 g per day (maximum up to 2.55-3 g per day).

The sugar-lowering effect of metformin is due to several mechanisms. A decrease in the level of glucose in the blood flowing from the liver indicates a decrease in both the rate and the total amount of glucose produced by the liver, which is a consequence of the inhibition of gluconeogenesis by inhibition of lipid oxidation. Under the influence of metformin, glucose utilization in the periphery increases due to the activation of the post-receptor mechanisms of insulin action and, in particular, tyrosine kinase and phosphotyrosine phosphatase. In addition, the peripheral effects of metformin are also mediated by its specific effect on the synthesis and pool of glucose transporters in the cell. ... Utilization of glucose in the intestinal mucosa increases. The number of glucose transporters (GLUT-1, GLUT-3 and GLUT-4) increases under the influence of metformin in the plasma membrane of both adipocytes and monocytes. The transport of glucose in the endothelium and vascular smooth muscles, as well as in the heart muscle, increases. It is this effect that explains the decrease in insulin resistance in patients with type 2 diabetes under the influence of metformin. An increase in insulin sensitivity is not accompanied by an increase in its secretion by the pancreas. At the same time, against the background of a decrease in insulin resistance, the basal level of insulin in the blood serum decreases. In patients treated with metformin, there is a decrease in body weight, in contrast to what can occur with an overdose of sulfonylureas and insulin. Moreover, the decrease in body weight occurs mainly due to a decrease in adipose tissue. In addition, metformin helps to lower serum lipids. At the same time, the concentration of total cholesterol, triglycerides, low and very low density lipoproteins decreases and, possibly, the level of high density lipoproteins increases, which has a positive effect on the course of macroangiopathy.

In recent years, it has been established that under the influence of metformin, fibrinolysis increases, which is reduced in patients with type 2 diabetes and is an additional factor in thrombus formation and vascular complications of diabetes. The main mechanism of action of metformin on increasing fibrinolysis is a decrease in the level of an inhibitor of plasminogen activator-1, which occurs in patients with type 2 diabetes, regardless of its dose. In addition to reducing the activity of the plasminogen activator-1 inhibitor, metformin also reduces the proliferation of smooth muscle cells in the vascular wall in vitro and the rate of atherogenesis in animals.

Metformin does not lower blood glucose below its normal level, which is why there are no hypoglycemic states in the treatment of diabetic patients with this drug.

It was noted above that sulfonylurea drugs stimulate insulin secretion, while metformin promotes glucose utilization by peripheral tissues, i.e. drugs, acting on various mechanisms, contribute to better compensation for diabetes. Combination therapy with sulfonylureas and metformin has been used for a long time and with good effect. Therefore, some companies have already mastered the production of combined action drugs.

Alpha glucosidase inhibitors (acarbose)- This is the third group of oral glucose-lowering drugs that have been widely used for the treatment of diabetes in the last 8-10 years in order to reduce the absorption of carbohydrates from the intestine and whose main action is associated with inhibition of the activity of enzymes involved in the digestion of carbohydrates. It is known that food carbohydrates, more than 60% of which are starch, in the gastrointestinal tract are first hydrolyzed by specific enzymes (glycosidases: beta-glucuronidase, beta-glucosaminidase, alpha-glucosidase, etc.) and then decompose to monosaccharides. The latter are absorbed through the intestinal mucosa and enter the central circulation. Recently, it has been shown that, in addition to the main action - inhibition of glucosidases, alpha-glucosidase inhibitors improve peripheral glucose utilization by increasing the expression of the GLUT-4 gene. The drug is well tolerated by patients and can be used to treat patients with type 2 diabetes in the case when it is not possible to achieve compensation for carbohydrate metabolism only on diet and adequate physical activity.

Typical doses of acarbose range from 50 mg per day, gradually increasing to 50 mg 3 times a day and then up to 100 mg 3 times a day. In this case, it is possible to avoid such undesirable phenomena as discomfort in the gastrointestinal tract, flatulence, and loose stools. The drug must be taken with the first sip of food (i.e. with meals). With acarbose monotherapy, hypoglycemia is absent.

Insulin action potentiators (or sensitizers) increase the sensitivity of peripheral tissues to insulin. The drugs in this group include glitazones or thiazolidinediones - pioglitazone and rosigditazone.

Algorithm for the treatment of type 2 diabetes

Thus, the modern algorithm for the treatment of type 2 diabetes includes: diet therapy, lifestyle changes (regular physical activity, smoking cessation, patient education), and in the absence of an effect, additional use of acarbose. In the presence of obesity, anorectics may be recommended. In case of insufficient effect from taking acarbose with overweight (ideal body weight 30 kg / m2 or more), combined treatment with metformin or sulfonylurea preparations (with ideal body weight up to 30 kg / m2). In these cases, a combination of metformin with sulfourea drugs (in case of excess weight) is possible. Insulin sensitizers (pioglitazone, usually 30 mg once daily) can be used alone or in combination with sulfonylureas and metformin. All of the listed oral hypoglycemic drugs can be used as monotherapy or in combination.

In case of an unsatisfactory effect of the treatment carried out, insulin therapy is indicated in the future. The criteria for prescribing insulin therapy for type 2 diabetes are: the lack of diabetes compensation when using diet therapy in combination with glucosidase inhibitors, biguanides, insulin sensitizers or insulin secretogens (sulfonylureas and drugs, derivatives of amino acids) and the so-called secondary insulin resistance to oral drugs.

According to various authors, secondary resistance to sulfonylureas occurs in 5-20% of patients with diabetes, and is associated with a decrease in residual insulin secretion. Secondary resistance to oral drugs after 1 year from the onset of the disease is detected in 4.1% of patients, and after 3 years - in 11.4%.

The study of the pathogenesis of secondary resistance to oral drugs has made it possible to establish its various mechanisms. In some patients, secondary resistance to hypoglycemic oral drugs occurs with reduced residual secretion of insulin and C-peptide, while antibodies to cellular antigens of the islets of the pancreas are absent. Based on the features clinical course diseases, these patients can be divided into 2 groups: 1) patients with type 2 diabetes with temporary insulin demand; 2) patients with a constant need for insulin or even with insulin dependence (LADA subtype).

The first group consists of patients with diabetes for 10 years or more and overweight. To compensate for carbohydrate metabolism, in these cases, two treatment tactics... The first is a complete transfer of patients to insulin therapy for a short time (2.5-4 months). This time is enough to remove glucose toxicity and lipotoxicity, restore the sensitivity of beta cells to sulfonylurea preparations and restore the reserve capacity of the islets of the pancreas. A prerequisite for removing glucose toxicity is to achieve full compensation for diabetes during the period of insulin therapy. In the future, patients are again transferred to oral therapy with good or satisfactory compensation results.

The second tactic is to conduct a combination therapy with insulin and oral antidiabetic drugs. For the treatment of patients with type 2 diabetes with secondary resistance to oral drugs, we have been using both treatment tactics for 10-12 years. We used combination therapy with insulin in a daily dose, usually no more than 30 U. per day (usually insulin of average duration of action). It is more advisable to prescribe insulin at night, i.e. at 22 or 23 o'clock. The onset of action of such a drug of insulin falls on the morning hours or at the time when there is an excessive formation of glucose by the liver. The result is a significant reduction in fasting blood glucose. In some cases, it is necessary to administer the indicated insulin preparations twice (in the morning and at 22-23 hours). During the day, to maintain the hypoglycemic effect, it is recommended to take sulfonylureas (glimepiride at a dose of 2-3 mg per day, glibenclamide at a dose of 10-15 mg per day or gliclazide at a dose of 60-180 mg per day). It is recommended to start insulin therapy with 10-12 units. and increase by 2-4. every 3-4 days until fasting glycemia drops to 5-6.8 mmol / l. Determination of glycemia during the day is necessary at least once a week during the selection of doses of antihyperglycemic drugs (insulin and oral drugs). It is imperative, in addition to determining fasting glycemia, to have data on the blood glucose content before lunch and dinner, as well as 1 hour after a meal.

In cases where patients require insulin therapy, the latter can be carried out in the mode of multiple injections or, more often, in the mode of double injections. In the latter case, we obtained good results when using insulin preparations of combined action. Combined action insulin preparations are administered before breakfast and before dinner.

In addition, the double-dose regimen can be used when using insulin preparations of short and medium duration of action. In this case, before breakfast, it is necessary to use short and medium-acting insulin, before dinner - a short-acting insulin preparation and before bedtime (at 22 or 23 hours) - medium-acting insulin. The ratio of short-acting insulin to medium-acting insulin in the morning is 1: 3 (25% and 75%), and in the evening - 1: 2 or even 1: 1. The regimen of multiple injections of insulin, which is necessary to control type 1 diabetes, has also been used to treat patients with type 2 diabetes. In these cases, both intermediate-acting insulin and long-acting insulin preparations can be used as basal insulin. However, there is practically no advantage of the multiple-injection regimen over the double-dose insulin regimen.

As for the insulin dose, to compensate for type 2 diabetes, a daily dose is required at the rate of 0.6-0.8 U per 1 kg of body weight. In some cases, the dose of the drug has to be increased to 0.9-1.0 U per 1 kg or even more. This is due to the insulin resistance so characteristic of type 2 diabetes. When diabetes compensation is achieved in such cases, the insulin demand decreases and, accordingly, the doses of insulin required to maintain diabetes compensation are reduced.

Achieving compensation for sugar diabetes mellitus 2 is a prerequisite for the prevention of vascular complications, early disability and increased mortality in this disease.