DIABETES MELLITUS
7.1. CLASSIFICATION OF DIABETES MELLITUS
Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia due to impaired secretion and / or effectiveness of insulin. Chronic hyperglycemia, which develops in diabetes, is accompanied by the development of complications from many organs and systems, primarily from the heart, blood vessels, eyes, kidneys and nerves. Diabetes in total affects 5-6% of the population. In economically developed countries of the world, every 10-15 years, the number of patients with diabetes increases by 2 times. Life expectancy in diabetes is reduced by 10-15%.
The causes of diabetes vary widely. In the vast majority of cases, diabetes develops either due to an absolute deficiency of insulin (type 1 diabetes mellitus - DM-1), or due to a decrease in the sensitivity of peripheral tissues to insulin in combination with secretory dysfunction of the β cells of the pancreas (type 2 diabetes mellitus - TD-2). In some cases, the attribution of the patient to DM-1 or DM-2 is difficult, however, in practice, compensation for diabetes is more significant, rather than accurately establishing its type. The etiological classification distinguishes four main clinical classes of diabetes (Table 7.1).
The most common SD-1 (item 7.5), SD-2 (item 7.6) and gestational SD (item 7.9) are discussed in separate chapters. Other specific types account for only about 1% of cases of diabetes. The etiology and pathogenesis of these types of diabetes seems to be more studied compared to DM-1 and especially DM-2. A number of variants of diabetes are due to monogenically inherited genetic defects in the function of β cells. This includes various variants of the autosomal dominant inherited syndrome MODY (English maturity onset diabetes of the young - adult-type diabetes in young people), which are characterized by a violation, but not the absence of insulin secretion with normal sensitivity to it of peripheral tissues.
Table. 7.1. Classification of diabetes mellitus
Casuistically rare are genetic defects in the action of insulin associated with a mutation of the insulin receptor (leprechaunism, Rabson-Mandehall syndrome). Diabetes naturally develops in diseases of the exocrine part of the pancreas, leading to the destruction of β cells (pancreatitis, pancreatectomy, cystic fibrosis, hemochromatosis), as well as in a number of endocrine diseases in which excessive production of controinsular hormones occurs (acromegaly, Cushing's syndrome). Drugs and chemicals (vacor, pentamidine, nicotinic acid, diazoxide, etc.) are rarely the cause of diabetes, but can contribute to the manifestation and decompensation of the disease in persons with insulin resistance. A number of infectious diseases (rubella, cytomegaly, coxsackie- and adenovirus infection) can be accompanied by the destruction of β cells, while in most patients immunogenetic markers of CD-1 are determined. Rare forms of immune-mediated diabetes include diabetes, which develops in patients with "stiff-rnan" syndrome (autoimmune neurological disease), as well as diabetes due to exposure to autoantibodies to insulin receptors. Various variants of diabetes with an increased frequency are found when
many genetic syndromes, in particular, in down, Klinefelter, Turner, Wolfram, Prader-Willi syndromes and a number of others.
7.2. CLINICAL ASPECTS OF THE PHYSIOLOGY OF CARBOHYDRATE METABOLISM
Insulin is synthesized and secreted by β cells of the islets of Langerhans of the pancreas (pancreas). In addition, the islets of Langerhans secrete glucagon (α cells), somatostatin (δ cells), and pancreatic polypeptide (PP cells). Hormones of islet cells interact with each other: glucagon normally stimulates insulin secretion, and somatostatin suppresses the secretion of insulin and glucagon. The insulin molecule consists of two polypeptide chains (A-chain - 21 amino acids; B-chain - 30 amino acids) (Fig. 7.1). Insulin synthesis begins with the formation of preproinsulin, which is broken down by the protease to form proinsulin. In the secretory granules of the Golgi apparatus, proinsulin is split into insulin and C-peptide, which are released into the blood during exocytosis (Fig. 7.2).
The main stimulant of insulin secretion is glucose. The release of insulin in response to an increase in blood glucose levels occurs biphasically (Fig. 7.3). The first, or acute, phase lasts a few minutes, and it is associated with the release of accumulated
Rice. 7.1. Scheme of the primary structure of the insulin molecule
Rice. 7.2. Scheme of insulin biosynthesis
insulin in the β cell between meals. The second phase continues until the glycemia level reaches the normal skinny (3.3-5.5 mmol / l). Similarly, the β cell is affected by sulfonylurea preparations.
Through the portal system, insulin reaches the liver - its main target organ. Hepatic receptors bind half of the secreted hormone. The other half, getting into the systemic circulation, reaches the muscles and adipose tissue. Most of the insulin (80%) undergoes proteolytic breakdown in the liver, the rest in the kidneys, and only a small amount is metabolized directly by muscle and fat cells. Normal pancreas
Rice. 7.3. Biphasic release of insulin under the influence of glucose
of an adult secretes 35-50 U of insulin per day, which is 0.6-1.2 U per 1 kg of body weight. This secretion is divided into food and basal. Food secretion of insulin responds to a postprandial rise in glucose levels, i.e. due to it, the neutralization of the hyperglycemic effect of food is ensured. The amount of dietary insulin roughly corresponds to the amount of carbohydrates taken - about 1-2.5 U
per 10-12 g of carbohydrates (1 bread unit - XE). Basal insulin secretion provides optimal levels of glycemia and anabolism in the intervals between meals and during sleep. Basal insulin is secreted at a rate of about 1 U / h, with prolonged physical exertion or prolonged fasting, it is significantly reduced. Dietary insulin accounts for at least 50-70% of daily insulin production (Fig. 7.4).
Insulin secretion is subject not only to food, but also to daily-
Rice. 7.4. The scheme of daily insulin production is normal
The need for insulin rises in the early morning hours, and then gradually decreases during the day. So, for breakfast for 1 XE, 2.0-2.5 U of insulin is secreted, for lunch - 1.0-1.5 U, and for dinner - 1.0 IU. One of the reasons for this change in insulin sensitivity is the high level of a number of counter-insular hormones (primarily cortisol) in the morning, which gradually drops to a minimum at the beginning of the night.
The main physiological effects of insulin are the stimulation of glucose transport through the cell membranes of insulin-dependent tissues. The main target organs of insulin are the liver, adipose tissue and muscles. Insulin-independent tissues, the intake of glucose in which does not depend on the effects of insulin, primarily include the central and peripheral nervous system, vascular endothelium, blood cells, etc. Insulin stimulates the synthesis of glycogen in the liver and muscles, the synthesis of fats in the liver and adipose tissue, the synthesis of proteins in the liver, muscles and other organs. All these changes are aimed at the utilization of glucose, which leads to a decrease in its level in the blood. The physiological antagonist of insulin is glucagon, which stimulates the mobilization of glycogen and fats from the depot; normally, the level of glucagon changes in the reciprocal production of insulin.
The biological effects of insulin are mediated by its receptors, which are located on target cells. The insulin receptor is a glycoprotein consisting of four subunits. With a high level of insulin in the blood, the number of its receptors on the principle of downward regulation decreases, which is accompanied by a decrease in the sensitivity of the cell to insulin. After the binding of insulin to the cell receptor, the resulting complex enters the cell. Further inside the muscle and fat cells, insulin causes the mobilization of intracellular vesicles, which contain the glucose transporter GLUT-4. As a result, the vesicles move to the cell surface, where GLUT-4 acts as an inlet for glucose. A similar effect on GLUT-4 is exerted by physical activity.
7.3. LABORATORY DIAGNOSTICS AND CRITERIA FOR COMPENSATING FOR DIABETES MELLITUS
Laboratory diagnosis of diabetes is based on the determination of blood glucose levels, while the diagnostic criteria are the same for all
types and variants of SD (Table 7.2). Data from other laboratory tests (glucosuria level, determination of the level of glycated hemoglobin) should not be used to verify the diagnosis of diabetes. The diagnosis of diabetes can be established on the basis of a two-time detection of one of three criteria:
1. With obvious symptoms of diabetes (polyuria, polydipsia) and the level of glucose in whole capillary blood is more than 11.1 mmol / l, regardless of the time of day and the previous meal.
2. When the level of glucose in whole capillary blood on an empty stomach is more than 6.1 mmol / l.
3. When the level of glucose in whole capillary blood 2 hours after taking 75 grams of glucose (oral glucose tolerance test) more than 11.1 mmol / l.
Table. 7.2. Criteria for diagnosing diabetes mellitus
The most important and significant test in the diagnosis of diabetes is to determine the level of fasting glycemia (at least 8 hours of fasting). In the Russian Federation, the level of glycemia, as a rule, is assessed in whole blood. In many countries, the determination of glucose levels is widely used
in the blood plasma. The oral glucose tolerance test (OGTT; determination of glucose levels 2 hours after ingestion of 75 grams of glucose dissolved in water) is given less importance in this regard. Nevertheless, on the basis of OGTT, a violation of glucose tolerance (NTG) is diagnosed. NTG is diagnosed if the level of glycemia of whole capillary blood on an empty stomach does not exceed 6.1 mmol / l, and 2 hours after the glucose load is above 7.8 mmol / L, but below 11.1 mmol / L. Another variant of carbohydrate metabolism disorders is impaired fasting glycemia (NGNT). The latter is established if the level of glycemia of whole capillary blood on an empty stomach is in the range of 5.6-6.0 mmol / l, and 2 hours after loading with glucose less than 7.8 mmol / l). NTG and NGNT are currently combined with the term prediabetes, since both categories of patients have a high risk of diabetes and the development of diabetic macroangiopathy.
For the diagnosis of diabetes, the level of glycemia should be determined by standard laboratory methods. When interpreting glycemic indicators, it should be borne in mind that on an empty stomach, the level of glucose in whole venous blood corresponds to its level in the whole capillary. After eating or OGTT, its level in venous blood is about 1.1 mmol / l lower than in capillary blood. Plasma glucose is about 0.84 mmol/L higher than in whole blood. In order to assess the compensation and adequacy of diabetes therapy, the level of glycemia in capillary blood is assessed using portable glucometers by the patients themselves, their relatives or medical personnel.
With any type of diabetes, as well as with a significant load of glucose, glucosuria can develop, which is a consequence of exceeding the threshold of glucose reabsorption from primary urine. The threshold of glucose reabsorption varies significantly individually (≈ 9-10 mmol / l). As a separate indicator of glucosuria for the diagnosis of diabetes should not be used. Normally, except in cases of significant nutritional load with refined carbohydrates, glycosuria does not occur.
The production of ketone bodies (acetone, acetoacetate, β-hydroxybutyrate) is significantly intensified with absolute insulin deficiency. With decompensation of DM-1, pronounced ketonuria can be determined (examined using test strips that are dipped into the urine). Mild (trace) ketonuria can be determined in healthy people with fasting and a carbohydrate-free diet.
An important laboratory indicator that is used for the differential diagnosis of types of diabetes, as well as for detecting the formation of insulin deficiency in patients with T2DM, is the level of C-peptide. By the level of C-peptide in the blood, it is possible to indirectly judge the insulin-secreting ability of β cells of the pancreas. The latter produce proinsulin, from which C-peptide is cleaved before secretion, which enters the blood in equal quantities with insulin. Insulin is 50% bound in the liver and has a half-life in the peripheral blood of about 4 min. C-peptide is not removed from the bloodstream by the liver and has a half-life in the blood of about 30 min. In addition, it is not bound by cellular receptors in the periphery. Therefore, the determination of the level of C-peptide is a more reliable test for assessing the function of the insular apparatus. The level of C-peptide is most informative to study against the background of stimulation tests (after eating or administering glucagon). The test is uninformative if it is carried out against the background of pronounced decompensation of diabetes, since severe hyperglycemia has a toxic effect on β cells (glucosotoxicity). Insulin therapy for the previous few days will not affect the test results in any way.
The main goal of the treatment of any type of diabetes is to prevent its late complications, which can be achieved against the background of its stable compensation for a number of parameters (Table 7.3). The main criterion for the quality of compensation of carbohydrate metabolism in diabetes is the level of glycated (glycosylated) hemoglobin (HbA1c). The latter is hemoglobin, non-covalently bound to glucose. In erythrocytes, glucose enters independently of insulin, and glycosylation of hemoglobin is an irreversible process, and its degree is directly proportional to the concentration of glucose with which it was in contact during the 120 days of its existence. A small part of hemoglobin is glycosylated and normal; with diabetes, it can be significantly increased. The level of HbA1c, in contrast to the level of glucose, which is constantly changing, integrally reflects glycemia over the past 3-4 months. It is at this interval that it is recommended to determine the level of HbA1c in order to assess the compensation of diabetes.
Chronic hyperglycemia is far from the only risk factor for the development and progression of late complications of diabetes. In this regard, the assessment of compensation for the MD is based on a complex
laboratory and instrumental research methods (Table 7.3). In addition to indicators characterizing the state of carbohydrate metabolism, the most important are the level of blood pressure and the lipid spectrum of the blood.
Table. 7.3. Criteria for compensation for diabetes mellitus
In addition to the above compensation criteria, an individual approach is necessary when planning the goals of diabetes treatment. The likelihood of development and progression of late complications of diabetes (especially microangiopathy) increases with increasing duration of the disease. Thus, if in children and young patients, whose diabetes experience in the future can reach several decades, it is necessary to achieve optimal glycemia indicators, then in patients in whom diabetes manifested in old and senile age, strict euglycemic compensation, which significantly increases the risk of hypoglycemia, is not always advisable.
7.4. INSULIN PREPARATIONS AND INSULIN THERAPY
Insulin preparations are vital for patients with TD-1; in addition, up to 40% of patients with T2DM receive them. Common indications for the appointment of insulin therapy for diabetes, many of which actually overlap one with another, include:
1. Type 1 diabetes mellitus
2. Pancreatectomy
3. Ketoacidotic and hyperosmolar coma
4. In diabetes mellitus type 2:
- obvious signs of insulin deficiency, such as progressive decrease in body weight and ketosis, severe hyperglycemia;
- major surgical interventions;
- acute macrovascular complications (stroke, myocardial infarction, gangrene, etc.) and severe infectious diseases, accompanied by decompensation of carbohydrate metabolism;
- the level of glycemia on an empty stomach is more than 15-18 mmol / l;
- lack of stable compensation, despite the appointment of maximum daily doses of various tableted hypoglycemic drugs;
- late stages of late complications of diabetes (severe polyneuropathy and retinopathy, chronic renal failure).
5. Inability to achieve compensation for gestational diabetes with the help of diet therapy.
By origin, insulin preparations can be classified into three groups:
• animal insulins (porcine);
• human insulins (semi-synthetic, genetically engineered);
• insulin analogues (lispro, aspart, glargine, detemir).
Advances in human insulin production technologies have led to the fact that the use of porcine insulins (differing from human insulin by one amino acid) has recently decreased significantly. Porcine insulin can be used to produce human insulin by a semi-synthetic method that involves replacing one different amino acid in its molecule. The highest quality is distinguished by genetically engineered human insulins. To obtain them, the part of the human genome responsible for the synthesis of insulin is associated with the genome of E. coli or yeast culture, as a result of which the latter begin to produce human insulin. The creation of insulin analogues by permutations of various amino acids pursued the goal of obtaining drugs with a given and most favorable pharmacokinetics. So, insulin lispro (Humalog) is an analogue
ultra-short-acting insulin, while its hypoglycemic effect develops already 15 minutes after the injection. Insulin analogue glargine (Lantus), on the contrary, is characterized by a long-term effect that lasts throughout the day, while a feature of the kinetics of the drug is the absence of pronounced peaks in plasma concentration. Most of the currently used preparations of insulin and its analogues are available in a concentration of 100 U / ml. According to the duration of action, insulins are divided into 4 main groups (Table 7.4):
Table. 7.4. Pharmacokinetics of drugs and insulin analogues
1. Ultra-short action (lispro, aspart).
2. Short-acting (simple human insulin).
3. Medium duration of action (insulins on neutral Hagedorn protamine).
4. Long-acting (glargine, detemir).
5. Mixtures of insulins of different duration of action (Novomix-30, Humulin-MZ, Humalog-Mix-25).
Ultrashort drugs [lispro (Humalog), aspart (Novorapid)] are insulin analogues. Their advantages are the rapid development of a hypoglycemic effect after injection (after 15 minutes), which allows you to make an injection immediately before meals or even immediately after a meal, as well as a short duration of action (less than 3 hours), which reduces the risk of hypoglycemia. Short-acting drugs (simple insulin, insulin-regular) are a solution containing insulin at a concentration of 100 U / ml. Injection of simple insulin is done 30 minutes before meals; the duration of action is about 4-6 hours. Ultrashort and short-acting drugs can be administered subcutaneously, intramuscularly and intravenously.
Among the drugs of medium duration of action, drugs on neutral Hagedorn protamine (NPH) are most often used. NPH is a protein that non-covalently adsorbs insulin, slowing its absorption from the subcutaneous depot. The effective duration of action of NPH insulins is usually about 12 hours; they are administered only subcutaneously. Insulin NPH is a suspension, and therefore, unlike simple insulin in the vial, it is cloudy, and with prolonged standing, a suspension is formed, which must be thoroughly mixed before injection. InsulinS of NPH, unlike other drugs of prolonged action, can be mixed in any ratio with short-acting insulin (simple insulin), while the pharmacokinetics of the components of the mixture will not change, since NPH will not bind additional amounts of simple insulin (Fig. 7.5). In addition, protamine is used to prepare standard mixtures of insulin analogues (Novomix-30, Humalog-Mix-25).
Among the long-acting drugs, insulin analogues glargine (Lantus) and detemir (Levemir) are currently actively used. A favorable feature of the pharmacokinetics of these drugs is that, unlike NPH insulins, they provide a more uniform and prolonged intake of the drug from the subcutaneous depot. In this regard, glargine can be prescribed only once a day, while almost regardless of the time of day.
Rice. 7.5. Pharmacokinetics of various insulin preparations:
(a) monocomponent; b) standard insulin mixtures
In addition to monocomponent insulin preparations, standard mixtures are widely used in clinical practice. As a rule, we are talking about mixtures of short or ultrashort insulin with insulin of medium duration of action. For example, the drug "Humulin-MZ" contains in one vial 30% of simple insulin and 70% of insulin of NPH; the drug "Novomix-30" contains 30% insulin aspart and 70% crystalline protamine suspension of insulin aspart; the drug "Humalog-Mix-25" contains 25% insulin lispro and 75% protamine suspension of insulin lispro. Advantage
standard insulin mixtures are the replacement of two injections with one and a slightly greater accuracy of the dosage components of the mixture; the disadvantage is the impossibility of individual dosing of individual components of the mixture. This determines the preference for the use of standard insulin mixtures for the treatment of TD-2 or in the so-called traditional insulin therapy (the appointment of fixed doses of insulin), while for intensive insulin therapy (flexible dose selection depending on glycemia and the amount of carbohydrates in food), the use of monocomponent drugs is preferable.
The key to successful insulin therapy is strict adherence to the injection technique. There are several ways to administer insulin. The simplest and at the same time reliable method is injections using an insulin syringe. A more convenient way to administer insulin is injection using a syringe pen, which is a combined device containing an insulin reservoir (cartridge), a dosing system and a needle with an injector.
For maintenance therapy (when it comes to severe decompensation of diabetes or critical conditions), insulin is administered subcutaneously. Injections of short-acting insulin are recommended to be done into the subcutaneous fatty tissue of the abdomen, insulin of prolonged action - into the fiber of the thigh or shoulder (Fig. 7.6 a). Injections are made deep into the subcutaneous tissue through widely compressed skin at an angle of 45 ° (Fig. 7.6 b). The patient should be recommended a daily change of insulin injection sites within one area in order to prevent the development of lipodystrophy.
Factors affecting the rate of absorption of insulin from the subcutaneous depot include the dose of insulin (increasing the dose increases the duration of absorption), the injection site (absorption faster from the abdominal fiber), ambient temperature (warming and massage of the injection site accelerates absorption).
A more complex method of administration, which, nevertheless, in many patients allows to achieve good treatment results, is the use of an insulin dispenser, or a system for continuous subcutaneous insulin administration. The dispenser is a portable device consisting of a computer that sets the mode of insulin supply, as well as an insulin supply system carried out through a catheter and a miniature needle to the subcutaneous
Rice. 7.6. Insulin injections: a) typical injection sites; b) the position of the insulin syringe needle at injection
fatty tissue. With the help of a dispenser, continuous basal administration of short-acting or ultra-short-acting insulin is carried out (a speed of the order of 0.5-1 U / h), and before eating, depending on the carbohydrate content in it and the level of glycemia, the patient injects the necessary bolus dose of the same short-acting insulin. The advantage of insulin therapy with a dispenser is the introduction of insulin alone of short (or even ultra-short) action, which in itself is somewhat more physiological, since the absorption of prolonged insulin preparations undergoes large fluctuations; therefore, the continuous administration of short-acting insulin is a more manageable process. The disadvantage of insulin therapy with the help of a dispenser is the need for constant wearing of the device, as well as a long stay of the injection needle in the subcutaneous tissue, which requires periodic monitoring of the insulin supply process. Insulin therapy with a dispenser is primarily indicated for patients with TD-1 who are ready to master the technique of its management. Especially in this regard, attention should be paid to patients with a pronounced phenomenon of "morning dawn", as well as to pregnant and pregnancy-planning patients with TD-1 and patients with diabetes.
ants with a disordered lifestyle (the possibility of a more flexible diet).
7.5. TYPE 1 DIABETES MELLITUS
TD-1 is an organ-specific autoimmune disease that leads to the destruction of insulin-producing β cells of the islets of the pancreas, manifested by an absolute deficiency of insulin. In some cases, patients with obvious TD-1 lack markers of autoimmune damage to β cells (idiopathic CD-1).
Aetiology
TD-1 is a disease with a hereditary predisposition, but its contribution to the development of the disease is small (determines its development by about 1 / z). Concordance in identical twins for CD-1 is only 36%. The probability of developing TD-1 in a child with a sick mother is 1-2%, father - 3-6%, brother or sister - 6%. One or more humoral markers of autoimmune lesions of β cells, which include antibodies to the islets of the pancreas, antibodies to glutamate decarboxylase (GAD65) and antibodies to tyrosine phosphatase (IA-2 and ΙΑ-2β), are found in 85-90% of patients. Nevertheless, the main importance in the destruction of β cells is attached to the factors of cellular immunity. CD-1 is associated with HLA haplotypes such as DQA and DQB, with some HLA-DR/DQ alleles being predisposing to the development of the disease, while others are protective. With an increased frequency, DM-1 is combined with other autoimmune endocrine (autoimmune thyroiditis, Addison's disease) and non-endocrine diseases, such as alopecia, vitiligo, Crohn's disease, rheumatic diseases (Table 7.5).
Pathogenesis
TD-1 manifests itself when destroyed by an autoimmune process of 80-90% of β cells. The speed and intensity of this process can vary significantly. Most often, in the typical course of the disease in children and young people, this process proceeds quite quickly with the subsequent rapid manifestation of the disease, in which only a few weeks can pass from the appearance of the first clinical symptoms to the development of ketoacidosis (up to ketoacidotic coma).
Table. 7.5. Type 1 diabetes mellitus
Continuation of Table. 7.5
In other, much rarer cases, as a rule, in adults over 40 years of age, the disease can proceed latently (latent autoimmune diabetes of adults - LADA), while in the debut of the disease, such patients are often diagnosed with TD-2, and for several years, compensation for diabetes can be achieved by prescribing sulfonylurea preparations. But in the future, usually after 3 years, there are signs of absolute insulin deficiency (weight loss, ketonuria, severe hyperglycemia, despite taking tableted hypoglycemic drugs).
The basis of the pathogenesis of T-1, as indicated, is an absolute deficiency of insulin. The impossibility of glucose entering insulin-dependent tissues (fat and muscle) leads to energy deficiency, as a result of which lipolysis and proteolysis are intensified, with which weight loss is associated. An increase in the level of glycemia causes hyperosmolarity, which is accompanied by osmotic diuresis and severe dehydration. In conditions of insulin deficiency and energy deficiency, the production of contrainsular hormones (glucagon, cortisol, growth hormone) is disinhibited, which, despite the increasing glycemia, causes stimulation of gluconeogenesis. Increased lipolysis in adipose tissue leads to a significant increase in the concentration of free fatty acids. With insulin deficiency, the liposynthetic ability of the liver is suppressed, and freedom is released.
Fatty acids are beginning to be incorporated into ketogenesis. The accumulation of ketone bodies leads to the development of diabetic ketosis, and later - ketoacidosis. With a progressive increase in dehydration and acidosis, a coma develops (see paragraph 7.7.1), which, in the absence of insulin therapy and rehydration, inevitably ends in death.
Epidemiology
TD-1 accounts for about 1.5-2% of all cases of diabetes, and this relative figure will continue to decrease due to the rapid increase in the incidence of TD-2. The risk of developing TD-1 throughout life in a representative of the white race is about 0.4%. The incidence of TD-1 increases by 3% per year: by 1.5% - due to new cases and by another 1.5% - due to an increase in the life expectancy of patients. The prevalence of TD-1 varies depending on the ethnic composition of the population. For 2000, it was 0.02% in Africa, 0.1% in South Asia, South and Central America, and 0.2% in Europe and North America. The highest incidence of TD-1 is in Finland and Sweden (30-35 cases per 100 thousand people per year), and the lowest in Japan, China and Korea (0.5-2.0 cases, respectively). The age peak of the manifestation of SD-1 corresponds to about 10-13 years. In the vast majority of cases, TD-1 manifests itself up to 40 years.
Clinical manifestations
In typical cases, especially in children and young people, TD-1 debuts with a vivid clinical picture that develops over several months or even weeks. The manifestation of TD-1 can provoke infectious and other concomitant diseases. Symptoms common to all types of diabetes associated with hyperglycemia are characteristic: polydipsia, polyuria, skin itching, but with DM-1 they are very pronounced. So, throughout the day, patients can drink and secrete up to 5-10 liters of fluid. A symptom specific to TD-1, which is due to an absolute deficiency of insulin, is weight loss, reaching 10-15 kg for 1-2 months. Characterized by pronounced general and muscle weakness, decreased performance, drowsiness. At the beginning of the disease, some patients may experience an increase in appetite, which is replaced by anorexia as ketoacidosis develops. The latter is characterized by the appearance of the smell of acetone (or fruity odor) from the mouth, nausea-
note, vomiting, often abdominal pain (pseudoperitonitis), severe dehydration and ends with the development of a coma (see paragraph 7.7.1). In some cases, the first manifestation of DM-1 in children is a progressive impairment of consciousness up to coma against the background of concomitant diseases, usually infectious or acute surgical pathology.
In relatively rare cases of the development of TD-1 in persons older than 35-40 years (latent autoimmune diabetes of adults), the disease may not manifest so clearly (moderate polydipsia and polyuria, lack of weight loss) and even be detected by chance during routine determination of the level of glycemia. In these cases, the patient is often diagnosed with TD-2 at the beginning and prescribed tableted hypoglycemic drugs (TSP), which for some time provide acceptable compensation for diabetes. Nevertheless, for several years (often within a year), the patient has symptoms due to the growing absolute deficiency of insulin: weight loss, the inability to maintain normal glycemia against the background of TSP, ketosis, ketoacidosis.
Diagnostics
Given that DM-1 has a vivid clinical picture, and is also a relatively rare disease, screening determination of the level of glycemia for the purpose of diagnosing TD-1 is not indicated. The likelihood of developing the disease in the closest relatives of patients is low, which, together with the lack of effective methods of primary prevention of TD-1, determines the inexpediency of studying immunogenetic markers of the disease in them. Diagnosis of TD-1 in the vast majority of cases is based on the detection of significant hyperglycemia in patients with pronounced clinical manifestations of absolute insulin deficiency. OGTT for the purpose of diagnosing CD-1 has to be carried out very rarely.
Differential diagnostics
In doubtful cases (detection of moderate hyperglycemia in the absence of obvious clinical manifestations, manifestation at a relatively young age), as well as for the purpose of differential diagnosis with other types of diabetes, the determination of the level of C-peptide (basal and 2 hours after a meal) is used. Indirect diagnostic value in doubtful cases may have the determination of immunological markers of DM-1 - antibodies to islets
Pancreas, glutamate decarboxylase (GAD65) and tyrosine phosphatase (IA-2 and IA-2β). Differential diagnosis of DM-1 and DM-2 is presented in Table. 7.6.
Table. 7.6. Differential diagnostics and differences between DM-1 and DM-2
Treatment
Treatment of any type of diabetes is based on three basic principles: hypoglycemic therapy (with TD-1 - insulin therapy), diet and patient education. Insulin therapy for TD-1 is of a substitution nature and its goal is to maximize the imitation of the physiological production of the hormone in order to achieve the accepted compensation criteria (Table 7.3). Intensive insulin therapy is closest to the physiological secretion of insulin. The need for insulin, corresponding to its basal secretion, is provided by two injections of insulin of medium duration of action (morning and evening) or one injection of long-acting insulin (glargine). The total dose of basal insu-
lina should not exceed half of the total daily requirement for the drug. Food or bolus insulin secretion is replaced by short- or ultra-short-acting insulin injections before each meal, and its dose is calculated based on the amount of carbohydrates that are expected to be taken during the upcoming meal, and the available level of glycemia, determined by the patient using a glucometer before each insulin injection (Fig. 7.7).
The approximate scheme of intensive insulin therapy, which will change almost every day, can be presented as follows. It is assumed that the daily need for insulin is about 0.5-0.7 U per 1 kg of body weight (for a patient with a body weight of 70 kg about 35-50 U). About 1 / z - 1/2 of this dose will be insulin of prolonged action (20-25 U), 1/2 - 2 / z insulin of short or ultrashort action. The dose of insulin NPH is divided into 2 injections: in the morning 2 / z of its dose (12 U), in the evening - 1 / z (8-10 U).
The purpose of the first stage of the selection of insulin therapy is to normalize the level of fasting glucose. The evening dose of insulin NPH is usually administered at 22-23 hours, the morning dose along with an injection of short-acting insulin before breakfast. When selecting the evening dose of insulin NPH, it is necessary to keep in mind the possibility of developing a number of
Rice. 7.7. Scheme of intensive insulin therapy
enough typical phenomena. The cause of morning hyperglycemia may be the insufficient dose of insulin of prolonged action, since by the morning the need for insulin increases significantly (the phenomenon of "morning dawn"). In addition to the insufficiency of the dose to morning hyperglycemia, its excess can lead to its excess - the phenomenon of Somogyi (Somogyi), posthypoglycemic hyperglycemia. This phenomenon is explained by the fact that the maximum sensitivity of tissues to insulin is noted between 2 and 4 o'clock in the morning. It is at this time that the level of the main contra-insular hormones (cortisol, growth hormone, etc.) is normally the lowest. If the evening dose of insulin of prolonged action is excessive, then hypoglycemia develops at this time. Clinically, it can manifest itself as a bad dream with nightmares, unconscious actions in a dream, morning headache and weakness. The development of hypoglycemia at this time causes a significant compensatory release of glucagon and other contrainsular hormones, followed by hyperglycemia in the morning. If in this situation you do not reduce, but increase the dose of prolonged insulin administered in the evening, nocturnal hypoglycemia and morning hyperglycemia will be aggravated, which ultimately can lead to chronic insulin overdose syndrome (Somogyi syndrome), which is a combination of obesity with chronic decompensation of diabetes, frequent hypoglycemia and progressive late complications. To diagnose the phenomenon of Somogyi, it is necessary to study the level of glycemia around 3 o'clock in the morning, which is an integral component of the selection of insulin therapy. If the reduction of the evening dose of NPH to a safe in terms of the development of nocturnal hypoglycemia is accompanied by hyperglycemia in the morning (the phenomenon of morning dawn), the patient should be recommended an earlier rise (6-7 in the morning), while the insulin injected at night still continues to maintain a normal level of glycemia.
A second injection of NPH insulin is usually given before breakfast along with a morning injection of short-acting (ultra-short)-acting insulin. In this case, the dose is selected mainly on the basis of indicators of the level of glycemia before the main daily meals (lunch, dinner); in addition, it can limit the development of hypoglycemia in the intervals between meals, for example, at noon, between breakfast and lunch.
The entire dose of insulin of prolonged action (glargine) is administered once a day, and it does not matter at what time. Kinetics
insulin glargine and detemir is more favorable in terms of the risk of developing hypoglycemia, including nocturnal.
The dose of short-acting or ultra-short-acting insulin even on the patient's first day of insulin appointment will depend on the amount of carbohydrates consumed (bread units) and the level of glycemia before injection. Conventionally, based on the daily rhythm of insulin secretion in the norm, about 1/
4
of the dose of short-acting insulin (6-8 IU) is reserved for dinner, the remaining dose will be approximately equally divided into breakfast and lunch (10-12 IU). The higher the baseline glycemia level, the less it will decrease per unit of insulin administered. A short-acting insulin injection is done 30 minutes before a meal, ultra-short-acting immediately before a meal or even immediately after a meal. The adequacy of the dose of short-acting insulin is assessed by glycemia 2 hours after a meal and before the next meal.
To calculate the dose of insulin with intensive insulin therapy, it is enough to count the XE number, based only on the carbohydrate component. At the same time, not all carbohydrate-containing products are taken into account, but only the so-called counted ones. The latter include potatoes, cereal products, fruits, liquid dairy and sweet products. Products containing indigestible carbohydrates (most vegetables) are not taken into account. Special metabolic tables have been developed, with the help of which, expressing the amount of carbohydrates in XE, it is possible to calculate the required dose of insulin. One XE corresponds to 10-12 g of carbohydrates (Table 10.7).
After a meal containing 1 XE, the level of glycemia increases by 1.6-2.2 mmol / l, i.e. by about as much as the glucose level decreases with the introduction of 1 U of insulin. In other words, for each XE contained in the food that is planned to be eaten, it is necessary to pre-administer (depending on the time of day) about 1 U of insulin. In addition, it is necessary to take into account the results of self-monitoring of the level of glycemia, which is made before each injection, and the time of day (about 2 U of insulin per 1 XE in the morning and at lunch, 1 U per 1 XE - for dinner). So, if hyperglycemia is detected, the dose of insulin, calculated in accordance with the upcoming meal (according to the number XE), should be increased, and vice versa, if hypoglycemia is detected, less insulin is administered.
Table. 7.7. Equivalent replacement of products constituting 1 XE
For example, if a patient has a glycemia level of 7 mmol / L 30 minutes before the planned dinner containing 5 XE, he needs to inject 1 U of insulin in order for the glycemia to decrease to a normal level: from 7 mmol / L to about 5 mmol / L. In addition, 5 U of insulin must be injected on the coating of 5 XE. Thus, the patient in this case will inject 6 U of short-acting or ultra-short-acting insulin.
After the manifestation of TD-1 and the beginning of insulin therapy for a sufficiently long time, the need for insulin may be small and be less than 0.3-0.4 U / kg. This period is referred to as the phase of remission, or "honeymoon". After a period of hyperglycemia and ketoacidosis, which suppress the secretion of insulin by 10-15% of the remaining β cells, compensation for hormonal metabolic disorders with the introduction of insulin restores the function of these cells, which then take on the provision of the body with insulin at a minimum level. This period can last from a few weeks to several years, but ultimately, due to the autoimmune destruction of the remaining β cells, the "honeymoon" ends.
The diet for TD-1 in trained patients who have the skills of self-control and selection of insulin dose can be liberalized, i.e. approaching free. If the patient does not have an excess or deficiency of body weight, the diet should be
isocaloric. The main component of food with TD-1 are carbohydrates, which should account for about 65% of the daily calorie. Preference should be given to products containing complex, slowly absorbed carbohydrates, as well as foods rich in dietary fiber. Foods containing easily digestible carbohydrates (flour, sweet) should be avoided. The proportion of proteins should be reduced to 10-35%, which helps to reduce the risk of developing microangiopathy, and the proportion of fats - up to 25-35%, while marginal fats should account for up to 7% of calories, which reduces the risk of developing atherosclerosis. In addition, it is necessary to avoid taking alcoholic beverages, especially strong ones.
An integral component of working with a patient with DM-1 and the key to its effective compensation is patient education. Throughout life, the patient must independently change the dose of insulin on his own, depending on numerous factors. Obviously, this requires the possession of certain skills that the patient needs to be taught. The "School of patients with DM-1" is organized in endocrinological hospitals or on an outpatient basis and is 5-7 structured classes in which a doctor or specially trained nurse interactively using various visual aids teaches patients the principles of self-control.
Forecast
In the absence of insulin therapy, a patient with DM-1 inevitably dies from ketoacidotic coma. With inadequate insulin therapy, against the background of which the criteria for compensating for diabetes are not achieved and the patient is in a state of chronic hyperglycemia (Table 7.3), late complications begin to develop and progress (clause 7.8). With TD-1, the manifestations of diabetic microangiopathy (nephropathy and retinopathy) and neuropathy (diabetic foot syndrome) are of the greatest clinical importance in this regard. Macroangiopathy in TD-1 comes to the fore relatively rarely.
7.6. TYPE 2 DIABETES MELLITUS
Type 2 diabetes mellitus is a chronic disease manifested by a violation of carbohydrate metabolism with the development of hyperglycemia due to insulin resistance and secretory dysfunction of β cells,
as well as lipid metabolism with the development of atherosclerosis. Since the main cause of death and disability of patients are complications of systemic atherosclerosis, TD-2 is sometimes called cardiovascular disease.
Table. 7.8. Type 2 diabetes mellitus
Aetiology
DM-2 is a multifactorial disease with a hereditary predisposition. Concordance for TD-2 in identical twins reaches 80% or more. Most patients with T-2 diabetes indicate the presence of DM-2 in the closest relatives; in the presence of TD-2 in one of the parents, the probability of its development in the offspring throughout life is 40%. Any one gene, the polymorphism of which determines the predisposition to T-2D, was not found. Of great importance in the implementation of hereditary predisposition to DM-2 are environmental factors, primarily lifestyle features. Risk factors for the development of DM-2 are:
- obesity, especially visceral (see paragraph 11.2);
- ethnicity (especially when changing the traditional way of life to the western one);
- SD-2 in the next of kin;
- sedentary lifestyle;
- diet features (high intake of refined carbohydrates and low fiber content);
- arterial hypertension.
Pathogenesis
Pathogenetically, DM-2 is a heterogeneous group of metabolic disorders, which determines its significant clinical heterogeneity. The basis of its pathogenesis is insulin resistance (a decrease in insulin-mediated utilization of glucose by tissues), which is realized against the background of secretory dysfunction of β cells. Thus, there is a violation of the balance of insulin sensitivity and insulin secretion. Secretory dysfunction of β cells is to slow down the "early" secretory release of insulin in response to an increase in blood glucose levels. In this case, the 1st (fast) phase of secretion, which consists in emptying the vesicles with accumulated insulin, is virtually absent; The 2nd (slow) phase of secretion is carried out in response to stabilizing hyperglycemia constantly, in tonic mode, and, despite excessive insulin secretion, the level of glycemia against the background of insulin resistance does not normalize (Fig. 7.8).
The consequence of hyperinsulinemia is a decrease in the sensitivity and number of insulin receptors, as well as suppression
post-receptor mechanisms mediating the effects of insulin (insulin resistance). The content of the main glucose transporter in muscle and fat cells (GLUT-4) is reduced by 40% in persons with visceral obesity and by 80% in persons with diabetes-2. Due to insulin resistance of hepatocytes and portal hyperinsulinemia, hyperproduction of glucose by the liver occurs, and fasting hyperglycemia develops, which is detected in most patients with TD-2, including in the early stages of the disease.
By itself, hyperglycemia adversely affects the nature and level of secretory activity of β cells (glucosotoxicity). For many years and decades, the existing hyperglycemia ultimately leads to the depletion of insulin production by β cells and the patient may have some symptoms of insulin deficiency - weight loss, ketosis with concomitant infectious diseases. Nevertheless, the residual production of insulin, which is enough to prevent ketoacidosis, is almost always preserved with TD-2.
Epidemiology
T2DM determines the epidemiology of diabetes as a whole, as it accounts for about 98% of cases of this disease. The prevalence of T2DM varies from country to country and ethnic group. In European
Rice. 7.8. Secretory dysfunction of β cells in type 2 diabetes mellitus (loss of the 1st rapid phase of insulin secretion)
countries, the United States and the Russian Federation, it makes up about 5-6% of the population. With age, the incidence of T2DM increases: among adults, the prevalence of DM-2 is 10%, among people over 65 years of age it reaches 20%. The incidence of T2DM is 2.5 times higher among Native Americans and Hawaiians; among the Indians of the Pima tribe (Arizona), it reaches 50%. Among the rural populations of India, China, Chile and African countries that lead a traditional lifestyle, the prevalence of DM-2 is very low (less than 1%). On the other hand, among immigrants to Western industrial countries, it reaches a significant level. So, among immigrants from India and China living in the United States and Great Britain, the prevalence of TD-2 reaches 12-15%.
WHO predicts an increase in the number of people with diabetes in the world by 122% over the next 20 years (from 135 to 300 million). This is due to both the progressive aging of the population and the spread and aggravation of urbanized lifestyles. In recent years, there has been a significant "rejuvenation" of TD-2 and an increase in its incidence among children.
Clinical manifestations
In most cases, there are no pronounced clinical manifestations, and the diagnosis is established by routine determination of the level of glycemia. The disease usually manifests itself over the age of 40 years, while the vast majority of patients have obesity and other components of metabolic syndrome (see paragraph 11.2). Patients do not complain of a decrease in working capacity, if there are no other reasons for this. Complaints of thirst and polyuria rarely reach significant severity. Quite often, patients are concerned about skin and vaginal itching, in connection with which they turn to dermatologists and gynecologists. Since many years often pass from the real manifestation of TD-2 to diagnosis (on average about 7 years), in many patients at the time of detection of the disease, the symptoms and manifestations of late complications of diabetes dominate in the clinical picture. Moreover, the first treatment of a patient with DM-2 for medical help very often occurs in connection with late complications. Thus, patients can be hospitalized in surgical hospitals with ulcerative lesions of the legs (diabetic foot syndrome), turn to ophthalmologists in connection with a progressive decrease in vision (diabetic retinopathy), be hospitalized with heart attacks, induc-
tami, obliterating lesion of the vessels of the legs in institutions, where they first show hyperglycemia.
Diagnostics
Diagnostic criteria that are the same for all types of diabetes are presented in paragraph 7.3. The diagnosis of TD-2 in the vast majority of cases is based on the detection of hyperglycemia in persons with typical clinical signs of DM-2 (obesity, age over 40-45 years, positive family history of DM-2, other components of metabolic syndrome), in the absence of clinical and laboratory signs of absolute insulin deficiency (severe weight loss, ketosis). The combination of the high prevalence of DM-2, its characteristic prolonged asymptomatic course and the possibility of preventing its severe complications, subject to early diagnosis, predetermine the need for screening, i.e. conducting an examination to exclude TD-2 among persons without any symptoms of the disease. The main test, as indicated, is to determine the level of glycemia on an empty stomach. It is shown in the following situations:
1. In all people over the age of 45 years, especially with excess body weight (BMI more than 25 kg / m2) with an interval of once every 3 years.
2. At a younger age, in the presence of excess body weight (BMI more than 25 kg / m2) and additional risk factors, which include:
- sedentary lifestyle;
- SD-2 in the next of kin;
- belonging to nationalities at high risk of developing CD-2 (African Americans, Hispanics, Native Americans, etc.);
- women who have given birth to a child weighing more than 4 kg and / or have a history of gestational diabetes;
- arterial hypertension (≥ 140/90 mm Hg);
- HDL level > 0.9 mmol / l and / or triglycerides > 2.8 mmol / l;
- polycystic ovary syndrome
- NTGs and NGNTs;
- cardiovascular diseases.
A significant increase in the incidence of T2D-2 among children dictates the need for screening the level of glycemia among children and adolescents (starting from 10 years with an interval of 2 years or with the beginning
Puberty, if it occurred at an earlier age), belonging to high-risk groups, which include children who are overweight (BMI and / or body weight > 85 percentile, corresponding to age, or weight more than 120% relative to the ideal) in combination with any two listed additional risk factors:
• CD-2 among first- or second-line relatives;
• belonging to high-risk nationalities;
• clinical manifestations associated with insulin resistance (acanthosis nigricans, arterial hypertension, dyslipidemia);
• Diabetes, including gestational, in the mother.
Differential diagnostics
The greatest clinical significance is the differential diagnosis of DM-2 and DM-1, the principles of which are described in clause 7.5 (Table 7.6). As indicated, in most cases it is based on the data of the clinical picture. In cases where the establishment of the type of diabetes is difficult, or there is a suspicion of some rare variant of diabetes, including within the framework of hereditary syndromes, the most important practical question that needs to be answered is whether the patient needs insulin therapy.
Treatment
The main components of the treatment of DM-2 are: diet therapy, expansion of physical activity, hypoglycemic therapy, prevention and treatment of late complications of diabetes. Since most patients with T2DM are obese, the diet should be aimed at weight loss (hypocaloric) and prevention of late complications, primarily macroangiopathy (atherosclerosis). A hypocaloric diet is necessary for all patients with excess body weight (BMI 25-29 kg / m2) or obesity (BMI > 30 kg / m2). In most cases, it should be recommended to reduce the daily calorie intake of food to 1000-1200 kcal for women and to 1200-1600 kcal for men. The recommended ratio of the main food components in DM-2 is similar to that of DM-1 (carbohydrates - 65%, proteins - 10-35%, fats up to 25-35%). The use of alcohol should be limited due to the fact that it is a significant source of additional calories, in addition, the intake of alcohol against the background of tera-
sulfonylurea and insulin preparations can provoke the development of hypoglycemia (see paragraph 7.7.3).
Recommendations for increasing physical activity should be individualized. In the beginning, aerobic exercise (walking, swimming) of moderate intensity lasting 30-45 minutes 3-5 times a day (about 150 minutes per week) is recommended. In the future, a gradual increase in physical activity is necessary, which significantly contributes to the reduction and normalization of body weight. In addition, physical activity helps to reduce insulin resistance and has a hypoglycemic effect. The combination of diet therapy and the expansion of physical activity without the appointment of hypoglycemic drugs makes it possible to maintain the compensation of diabetes in accordance with the established goals (Table 7.3) in approximately 5% of patients with TD-2.
Preparations for hypoglycemic therapy for DM-2 can be divided into four main groups.
I. Drugs that help reduce insulin resistance (sensitizers). This group includes metformin and thiazolidinediones. Metformin is the only currently used drug from the group of biguanides. The main components of the mechanism of its action are:
1. Suppression of gluconeogenesis in the liver (decrease in glucose production by the liver), which leads to a decrease in the level of fasting glycemia.
2. Reduction of insulin resistance (increased utilization of glucose by peripheral tissues, primarily muscles).
3. Activation of annaerobic glycolysis and reduction of glucose absorption in the small intestine.
Metformin is the first-choice drug of hypoglycemic therapy in patients with T2DM, obesity and fasting hyperglycemia. The initial dose is 500 mg at night or during dinner. In the future, the dose is gradually increased to 2-3 grams for 2-3 doses. Among the side effects, dyspeptic phenomena (diarrhea) are relatively common, which, as a rule, are transient and go away on their own after 1-2 weeks of taking the drug. Since metformin does not have a stimulating effect on insulin production, against the background of monotherapy with this drug, hypoglycemia is not
develop (its action is designated as antihyperglycemic, not hypoglycemic). Contraindications to the appointment of metformin are pregnancy, severe cardiac, hepatic, renal and other organ failure, as well as hypoxic conditions of another genesis. An extremely rare complication that occurs when metformin is prescribed without taking into account these contraindications, is lactic acidosis, which is a consequence of hyperactivation of anaerobic glycolysis.
Thiazolidinediones (pioglitazone, rosiglitazone) are agonists of γ receptors activated by the peroxisome proliferator (PPAR-γ). Thiazolidinediones activate the metabolism of glucose and lipids in muscle and adipose tissues, which leads to an increase in the activity of endogenous insulin, i.e. to the elimination of insulin resistance (insulin sensitizers). The daily dose of pioglitazone is 15-30 mg / day, rosiglitazone - 4-8 mg (for 1-2 doses). The combination of thiazolidinediones with metformin is very effective. Contraindication to the appointment of thiazolidinediones is an increase (2.5 times or more) in the level of hepatic transaminases. In addition to hepatotoxicity, the side effects of thiazolidinedione include fluid retention and edema, which often develop with a combination of drugs with insulin.
II. Drugs that affect the β cell and contribute to the enhancement of insulin secretion. This group includes sulfonylurea preparations and glinides (prandial glycemic regulators), which are used mainly to normalize the level of glycemia after eating. The main target of sulfonylurea (PSM) preparations are β cells of the pancreatic islets. PSMs bind on the membrane of β cells with specific receptors. This leads to the closure of ATP-dependent potassium channels and depolarization of the cell membrane, which in turn contributes to the opening of calcium channels. The intake of calcium inside β cells leads to their degranulation and the release of insulin into the blood. In clinical practice, quite a lot of PSMs are used, which differ in duration and severity of the hypoglycemic effect (Table 7.9).
Table. 7.9. Sulfonylurea preparations
The main and fairly frequent side effect of PSM is hypoglycemia (see paragraph 7.7.3). It can occur with an overdose of the drug, its cumulation (renal failure),
non-compliance with the diet (skipping meals, drinking alcohol) or regimen (significant physical exertion, before which the dose of PSM is not reduced or carbohydrates are not taken).
The group of glynides (prandial glycemic regulators) includes repaglinide (benzoic acid derivative; daily dose of 0.5-16 mg / day) and nateglinide (D-phenylalanine derivative; daily dose of 180-540 mg / day). After administration, the drugs quickly and reversibly interact with the sulfonylurea receptor on the β cell, resulting in a short increase in insulin levels, which mimics the first phase of its secretion normally. Drugs are taken 10-20 minutes before the main meals, usually 3 times a day.
III. Drugs that reduce the absorption of glucose in the intestine.
This group includes acarbose and guar resin. The mechanism of action of acarbose is a reversible blockade of α glycosidases of the small intestine, as a result of which the processes of sequential fermentation and absorption of carbohydrates slow down, the rate of resorption and glucose intake into the liver decreases and the level of postprandial glycemia decreases. The initial dose of acarbose is 50 mg 3 times a day, in the future, the dose can be increased to 100 mg 3 times a day; the drug is taken immediately before meals or during meals. The main side effect of acarbose is intestinal dyspepsia (diarrhea, flatulence), which is associated with the intake of unabsorbed carbohydrates into the colon. The hypoglycemic effect of acarbose is very moderate (Table 7.10).
In clinical practice, tableted hypoglycemic drugs are effectively combined with each other and with insulin preparations, since in most patients both lean and postprandial hyperglycemia are simultaneously determined. There are numerous fixed combinations of drugs in one tablet. Most often, metformin is combined with various PSMs in one tablet, as well as metformin with thiazolidinediones.
Table. 7.10. Mechanism of action and potential efficacy of tableted hypoglycemic drugs
IV. Insulins and insulin analogues
At a certain stage, insulin preparations begin to receive up to 30-40% of patients with T-2 diabetes. Indications for insulin therapy for T2DM are given at the beginning of paragraph 7.4. The most common option for transferring patients with TD-2 to insulin therapy is to prescribe insulin of prolonged action (insulin NPH, glargine or detemir) in combination with taken tableted hypoglycemic drugs. In a situation where the level of fasting glycemia cannot be controlled by the appointment of metformin or the latter is contraindicated, the patient is prescribed an evening (at night) injection of insulin. If it is impossible to control both skinny and postprandial glycemia with the help of tablet preparations, the patient is transferred to monoinsulin therapy. Usually, with TD-2, insulin therapy is carried out according to the so-called "traditional" scheme, which involves the appointment of fixed doses of long-acting and short-acting insulin. In this regard,
standard insulin mixtures containing short (ultrashort) and prolonged insulin in one vial are convenient. The choice of traditional insulin therapy is determined by the fact that with TD-2 it is often prescribed to elderly patients, whose training to independently change the dose of insulin is difficult. In addition, intensive insulin therapy, the purpose of which is to maintain the compensation of carbohydrate metabolism at a level approaching normoglycemia, carries an increased risk of hypoglycemia. If for young patients mild hypoglycemia does not pose a serious danger, in elderly patients with a reduced threshold of sensation of hypoglycemia, they can have very adverse consequences from the cardiovascular system. Young patients with T2DM, as well as patients who are promising in terms of the possibility of effective training, can be prescribed an intensive version of insulin therapy.
Forecast
The main cause of disability and death of patients with DM-2 are late complications (see paragraph 7.8), most often diabetic macroangiopathy. The risk of developing individual late complications is determined by a set of factors that are discussed in the relevant chapters. A universal risk factor for their development is chronic hyperglycemia. Thus, a decrease in the level of HbA1c in patients with T2D by 1% leads to a decrease in overall mortality by about 20%, by 2% and 3% - respectively, by about 40%.
and 60%.
7.7. ACUTE COMPLICATIONS OF DIABETES MELLITUS
7.7.1. Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) - decompensation of TD-1, due to absolute insulin deficiency, in the absence of timely treatment ending in ketoacidotic coma (QC) and death.
Aetiology
The cause of DKA is an absolute deficiency of insulin. One or another severity of DKA is determined in most patients at the time of manifestation of TD-1 (10-20% of all cases of DKA).
In a patient with an established diagnosis of DM-1, DKA can develop when insulin administration is discontinued, often by the patient himself (13% of cases of DKA), against the background of concomitant diseases, primarily infectious, in the absence of an increase in the dose of insulin
(30-40 %).
Table. 7.11. Diabetic ketoacidosis
Up to 20% of cases of DKA development in young patients with DM-1 are associated with psychological problems and / or eating disorders (fear of weight gain, fear of hypoglycemia, adolescent problems). A fairly common cause of ACAD in a number of countries is
cancellation of insulin by the patient himself due to the high cost of drugs for some segments of the population (table 7.11).
Pathogenesis
The pathogenesis of DKA is based on an absolute deficiency of insulin in combination with an increase in the production of contrainsular hormones, such as glucagon, catecholamines and cortisol. As a result, there is a significant increase in glucose production by the liver and a violation of its utilization by peripheral tissues, an increase in hyperglycemia and a violation of the osmolarity of the extracellular space. Insulin deficiency in combination with a relative excess of counterinsular hormones in DKA leads to the release of free fatty acids (lipolysis) into circulation and their inconstrained oxidation in the liver to ketone bodies (β-hydroxybutyrate, acetoacetate, acetone), resulting in hyperketonemia, and later metabolic acidosis. As a result of severe glycosuria, osmotic diuresis, dehydration, loss of sodium, potassium and other electrolytes develop (Fig. 7.9).
Epidemiology
The frequency of new cases of DKA is 5-8 per 1000 patients with TD-1 per year and directly depends on the level of organization of medical care for patients with diabetes. There are about 100,000 hospitalizations for DKA in the U.S. each year, with a cost of $13,000 per patient per hospitalization, more than $1 billion a year is spent annually on inpatient treatment for DKA. In the Russian Federation in 2005, DKA was recorded in 4.31% of children, 4.75% of adolescents and 0.33% of adult patients with TSD-1.
Clinical manifestations
The development of DKA, depending on the cause that caused it, can take from several weeks to a day. In most cases, DKA is preceded by symptoms of diabetes decompensation, but sometimes they may not have time to develop. Clinical symptoms of DKA include polyuria, polydipsia, weight loss, diffuse abdominal pain ("diabetic pseudoperitonitis"), dehydration, severe weakness, acetone odor from the mouth (or fruity smell), gradual clouding of consciousness. True coma in DKA has recently developed relatively rarely due to early diagnosis. Physical examination reveals signs of dehydration: decrease
Rice. 7.9. Pathogenesis of ketoacidotic coma
skin turgor and density of eyeballs, tachycardia, hypotension. In advanced cases, Kussmaul's breathing develops. More than 25% of patients with DKA develop vomiting, which may resemble coffee grounds in color.
Diagnostics
It is based on the data of the clinical picture, indications of the presence of diabetes-1 in the patient, as well as laboratory research data. DKA is characterized by hyperglycemia (in some cases insignificant), ketonuria, metabolic acidosis, hyperosmolarity (Table 7.12).
Table. 7.12. Laboratory diagnosis of acute complications of diabetes mellitus
When examining patients with acute decompensation of diabetes, it is necessary to determine the level of glycemia, creatinine and urea, electrolytes, on the basis of which the effective osmolarity is calculated. In addition, an assessment of the acid-base state is necessary. The effective osmolarity (EO) is calculated using the following formula: 2 * [Na+ (mEq/L) + glucose (mmol/L)]. Normally, the EO is 285 - 295 mOsm / l.
In most patients with DKA, leukocytosis is determined, the severity of which is proportional to the level of ketone bodies in the blood. Sodium levels are usually reduced due to the osmotic outflow of fluid from intracellular spaces to extracellular spaces in response to hyperglycemia. Less commonly, sodium levels can be reduced false positively as a consequence of severe hyper-
triglyceridemia. The level of serum potassium can initially be increased due to its movement from extracellular spaces.
Differential diagnostics
Other causes of loss of consciousness in patients with diabetes. Differential diagnosis with hyperosmolar coma, as a rule, does not cause difficulties (develops in elderly patients with diabetes-2) and does not have much clinical significance, because the principles of treatment of both conditions are similar. If it is impossible to quickly find out the cause of the loss of consciousness of a patient with diabetes, he is shown the introduction of glucose, because hypoglycemic conditions are much more common, and the rapid positive dynamics against the background of glucose injection in itself allows you to find out the cause of loss of consciousness.
Treatment
Treatment of DKA involves rehydration, correction of hyperglycemia, electrolyte disorders, as well as treatment of diseases that caused decompensation of diabetes. Treatment is most optimally carried out in the intensive care unit of a specialized medical institution. In adult patients without severe concomitant cardiac pathology, even at the prehospital stage, the introduction of an isotonic solution (0.9% NaCl) is recommended as a primary measure for rehydration at an approximate rate of a liter per hour (about 15-20 ml per kilogram of body weight per hour). Complete compensation for fluid deficiency, which in DKA is 100-200 ml per kg of body weight, should be achieved within the first day of treatment. With concomitant heart or kidney failure, this period of time should be increased. For children, the recommended volume of isotonic solution for rehydration therapy is 10-20 ml per kg of body weight per hour, while for the first 4 hours it should not exceed 50 ml per kg of body weight. Full rehydration is recommended to be achieved in about 48 hours. After the level of glycemia decreases to about 14 mmol / l against the background of parallel insulin therapy, they switch to transfusion of 10% glucose solution, which continues rehydration.
Currently, the concept of "small doses" of insulin in the treatment of DKA has been adopted. Only short-acting insulin is used. The most optimal use of intravenous insu-
Lina. Intramuscular administration of insulin, which is less effective, is possible only with moderate severity of DKA, with stable hemodynamics and with the impossibility of intravenous therapy. In the latter case, injections are made into the rectus abdominis muscle, while a needle for intramuscular injections is put on the insulin syringe (for reliable intramuscular contact), and insulin is dialed from the vial into the syringe through this needle.
Several options for intravenous insulin administration are possible. First, insulin can be injected "into the elastic band" of the infusion system, while the required amount of insulin is collected in an insulin syringe, after which 1 ml of isotonic solution gets into it. Up to reaching a glycemia level of 14 mmol / l, 6-10 U of short-acting insulin is administered to the patient every hour; in the future (in parallel with the change of the rehydration solution from isotonic to 10% glucose), depending on the hourly determined indicators of glycemia, the dose of insulin decreases to 4-8 U per hour. The recommended rate of decrease in glycemia levels should not exceed 5 mmol / l per hour. Another option for intravenous insulin therapy involves the use of a perfusor. To prepare a solution for a perfusor, the ratio is based on: 2 ml of 20% human albumin solution is added to 50 U of short-acting insulin, after which 50 mg of 0.9% isotonic solution is added. If the intramuscular route of insulin administration is chosen, 20 U of short-acting insulin is initially administered, after which 6 U is administered hourly, and after reaching a glycemia level of 14 mmol / l, the dose is reduced to 4 U per hour. After complete stabilization of hemodynamics and compensation of acid-base disorders, the patient is transferred to subcutaneous insulin injections.
As indicated, despite the significant deficiency of potassium in the body (total loss of 3-6 mmol / kg), with DKA, its level before the start of insulin therapy may be slightly increased. Nevertheless, the beginning of transfusion of potassium chloride solution is recommended to be carried out simultaneously with the start of insulin therapy, if the plasma potassium level is less than 5.5 mmol / L. Successful correction of potassium deficiency occurs only against the background of normalization of pH. At a low pH, the intake of potassium inside the cell is significantly reduced, and therefore, if possible, it is desirable to adapt the dose of transfused potassium chloride to a specific pH indicator (Table 7.13).
Table. 7.13. Scheme of correction of potassium deficiency
* The following data is used for calculation:
1 g KCl = 13.4 mmol; 1 mmol KCl = 0.075 g. In a 4% solution of COP1: in 100 ml - 4 g of COP1, in 25 ml - 1 g of COP1, in 10 ml 0.4 g of COP1.
The cause of decompensation of diabetes is often infectious diseases (pyelonephritis, infected ulcer in diabetic foot syndrome, pneumonia, sinusitis, etc.). There is a rule according to which with DKA antibiotic therapy is prescribed to almost all patients with subfebrile condition or fever, even in the absence of a visible focus of infection, since an increase in body temperature is not characteristic of DKA itself.
Forecast
Mortality in DKA is 0.5-5%, while most cases are due to late and unqualified provision of medical care. Mortality is highest (up to 50%) among elderly patients.
7.7.2. Hyperosmolar coma
Hyperosmolar coma (GOK) is a rare acute complication of DM-2, which develops due to severe dehydration and hyperglycemia against the background of the absence of absolute insulin deficiency, accompanied by high mortality (Table 7.14).
Aetiology
GOK usually develops in elderly patients with T-2 diabetes. Such patients are most often lonely, live without care, neglect their condition and self-control and take insufficient fluids. Often, infections (diabetic foot syndrome, pneumonia, acute pyelonephritis), brain disorders lead to decompensation.
blood circulation and other conditions, as a result of which patients do not move well, do not take hypoglycemic drugs and fluid.
Table. 7.14. Hyperosmolar coma (GOK)
Pathogenesis
Increasing hyperglycemia and osmotic diuresis cause pronounced dehydration, which for the above reasons is not replenished from the outside. The result of hyperglycemia and dehydration is plasma hyperosmolarity. An integral component of the pathogenesis of GOK is a relative deficiency of insulin and an excess of contrainsular hormones, however, the residual insulin secretion preserved in CD-2 is sufficient to suppress lipolysis and ketogenesis, as a result of which the development of ketoacidosis does not occur.
In some cases, moderate severity of acidosis can be determined as a result of hyperlactathemia against the background of tissue hypoperfusion. With severe hyperglycemia, in order to maintain osmotic balance in the cerebrospinal fluid, the sodium content coming from the brain cells increases, where potassium enters the exchange. The transmembrane potential of nerve cells is disturbed. Progressive confusion of consciousness develops in combination with a convulsive syndrome (Fig. 7.10).
Epidemiology
GOK accounts for 10-30% of acute hyperglycemic conditions in adult and elderly patients with TD-2. In about 2/
3
of cases, GOK develops in persons with previously undiagnosed diabetes.
Clinical manifestations
Features of the clinical picture of hyperosmolar coma are:
- a complex of signs and complications of dehydration and hypoperfusion: thirst, dryness of the mucous membranes, tachycardia, arterial hypotension, nausea, weakness, shock;
- focal and generalized convulsions;
- fever, nausea and vomiting (40-65% of cases);
- of the concomitant diseases and complications, deep vein thrombosis, pneumonia, cerebral circulation disorders, gastroparesis are often found.
Diagnostics
It is based on the data of the clinical picture, the age of the patient and the history of TD-2, severe hyperglycemia in the absence of ketonuria and ketoacidosis. Typical laboratory signs of GOK are presented in Table. 7.12.
Rice. 7.10. Pathogenesis of hyperosmolar coma
Differential diagnostics
Other acute conditions that develop in patients with diabetes, most often with concomitant pathology that led to severe decompensation of diabetes.
Treatment
Treatment and monitoring in GOK, with the exception of some features, do not differ from those described for ketoacidotic diabetic coma (clause 7.7.1):
• a larger volume of initial rehydration of 1.5-2 liters per 1 hour; 1 l - for the 2nd and 3rd hour, then 500 ml / h of isotonic sodium chloride solution;
• the need for the introduction of potassium-containing solutions, as a rule, is greater than with ketoacidotic coma;
• insulin therapy is similar to that of QC, but the need for insulin is less and the level of glycemia should be reduced no faster than 5 mmol / l per hour in order to avoid the development of cerebral edema;
• the introduction of a hypotonic solution (NaCl 0.45%) is best avoided (only with severe hypernatremia: > 155 mmol / l and / or effective osmolarity > 320 mOsm / l);
• there is no need for the introduction of bicarbonate (only in specialized intensive care units for acidosis with a pH of < 7.1).
Forecast
Mortality in GOK is high and is 15-60%. The worst prognosis in elderly patients with severe concomitant pathology, which, often, is the cause of decompensation of diabetes and the development of GOK.
7.7.3. Hypoglycemia
Hypoglycemia is a decrease in serum glucose levels (<2.2-2.8 mmol / l), accompanying a clinical syndrome characterized by signs of activation of the sympathetic nervous system and / or dysfunction of the central nervous system. Hypoglycemia as a laboratory phenomenon is not identical to the concept of "hypoglycemic symptoms", since laboratory data and the clinical picture do not always coincide.
Aetiology
- Overdose of insulin preparations and its analogues, as well as sulfonylurea preparations;
- insufficient food intake against the background of unchanged hypoglycemic therapy;
- reception of alcoholic beverages;
- physical activity against the background of unchanged hypoglycemic therapy and / or without additional intake of carbohydrates;
- the development of late complications of diabetes (autonomic neuropathy with gastroparesis, renal failure) and a number of other diseases (adrenal insufficiency, hypothyroidism, liver failure, malignant tumors) with unchanged hypoglycemic therapy (continued administration and cumulation of SSP against the background of renal failure, preservation of the previous dose of insulin);
- violation of the technique of insulin administration (intramuscular injection instead of subcutaneous);
- artifical hypoglycemia (conscious overdose of hypoglycemic drugs by the patient himself);
- organic hyperinsulinism - insulinoma (see paragraph 10.3).
Pathogenesis
The pathogenesis of hypoglycemia is to upset the balance between the flow of glucose into the blood, its utilization, the level of insulin and counterinsular hormones. Normally, with a glycemia level in the range of 4.2-4.7 mmol / l, the production and release of insulin from β cells are suppressed. A decrease in the level of glycemia of less than 3.9 mmol / l is accompanied by stimulation of the production of contra-insular hormones (glucagon, cortisol, growth hormone, adrenaline). Neuroglycopenic symptoms develop with a decrease in the level of glycemia of less than 2.5-2.8 mmol / L. With an overdose of insulin and / or sulfonylurea preparations, hypoglycemia develops due to the direct hypoglycemic action of an exogenous or endogenous hormone. In case of an overdose of sulfonylurea preparations, hypoglycemic symptoms can repeatedly recur after stopping the attack due to the fact that the duration of action of a number of drugs can reach a day or more. SCPs that do not have a stimulating effect on insulin production (metformin, thiazolidinediones) cannot cause hypoglycemia by themselves, but when they are added to sulfonylurea preparations or insulin, taking the latter in the previous dose can cause hypoglycemia due to cumulation of the hypoglycemic effect of combination therapy (Table 7.15).
Table. 7.15. Hypoglycemia
End of Table. 7.15
When taking alcohol, gluconeogenesis in the liver is suppressed, which is the most important factor counteracting hypoglycemia. Physical activity contributes to insulin-independent utilization of glucose, so that against the background of unchanged hypoglycemic therapy and / or in the absence of additional carbohydrate intake, hypoglycemia can cause hypoglycemia.
Epidemiology
Mild, rapidly stopping hypoglycemia in patients with T-1 diabetes receiving intensive insulin therapy can develop several times a week, and are relatively harmless. For one patient on intensive insulin therapy, there is 1 case of severe hypoglycemia per year. In most cases, hypoglycemia develops at night. With DM-2, 20% of patients receiving insulin and 6% receiving sulfonylurea preparations develop at least one episode of severe hypoglycemia for 10 years.
Clinical manifestations
There are two main groups of symptoms: adrenergic, associated with the activation of the sympathetic nervous system and the release of adrenaline by the adrenal glands, and neuroglycegenic, associated with impaired functioning of the central nervous system against the background of a deficiency of its main energy substrate. Adrenergic symptoms include: tachycardia, mydriasis; anxiety, aggressiveness; trembling, cold sweat, paresthesia; nausea, severe hunger, hypersalivation; diarrhea, profuse urination. Neuroglycopenic symptoms include asthenia,
decreased concentration, headache, fear, confusion, disorientation, hallucinations; speech, visual, behavioral disorders, amnesia, impaired consciousness, convulsions, transient paralysis, coma. There may be no clear dependence on the severity and sequence of the development of symptoms as hypoglycemia becomes heavier. Only adrenergic or only neuroglycopenic symptoms may occur. In some cases, despite the restoration of normoglycemia and ongoing therapy, patients can stay in a stuporous or even comatose state for several hours and even days. Prolonged hypoglycemia or its frequent episodes can lead to irreversible changes in the central nervous system (primarily in the cerebral cortex), the manifestations of which vary significantly from delirium and hallucinatory-paranoid episodes to typical epileptic seizures, the inevitable outcome of which is persistent dementia.
Hyperglycemia is subjectively tolerated by patients more easily than episodes of even mild hypoglycemia. Therefore, many patients, due to fear of hypoglycemia, consider it necessary to maintain glycemia at a relatively high level, which actually corresponds to the decompensation of the disease. Overcoming this stereotype sometimes requires considerable efforts of doctors and training staff.
Diagnostics
The clinical picture of hypoglycemia in a patient with diabetes in combination with laboratory (usually using a glucometer) detection of low blood glucose.
Differential diagnostics
Other causes leading to loss of consciousness. If the cause of loss of consciousness of a patient with diabetes is unknown and it is impossible to conduct an express analysis of the level of glycemia, he is shown the introduction of glucose. Often there is a need to find out the cause of the development of frequent hypoglycemia in patients with diabetes. Most often, they are the result of inadequate hypoglycemic therapy and a low level of knowledge of the patient about his disease. It should be remembered that a number of diseases (adrenal insufficiency, hypothyroidism, renal and hepatic insufficiency), including malignant tumors, can lead to a decrease in the need for hypoglycemic therapy up to its complete abolition ("disappeared diabetes").
Treatment
For the treatment of mild hypoglycemia, in which the patient is conscious and can help himself, it is usually enough to take food or liquid containing carbohydrates in the amount of 1-2 bread units (10-20 g of glucose). This amount is contained, for example, in 200 ml of sweet fruit juice. Drinks more effectively stop hypoglycemia, since in liquid form glucose is much more likely to be absorbed. If the symptoms continue to increase, despite the continued intake of carbohydrates, intravenous glucose or intramuscular glucagon is necessary. Similarly, severe hypoglycemia, which occurs with loss of consciousness, is treated. In this case, the patient is injected with about 50 ml of a 40% glucose solution intravenously. The introduction of glucose should be continued until the seizure is stopped and glycemia is normalized, although a larger dose - up to 100 ml or more, as a rule, is not required. Glucagon is administered (usually prepared in the factory with a filled syringe) intramuscularly or subcutaneously. After a few minutes, the level of glycemia due to the induction of glycogenolysis by glucagon normalizes. However, this does not always happen: with a high level of insulin in the blood, glucagon is ineffective. The half-life of glucagon is shorter than that of insulin. In alcoholism and liver disease, glycogen synthesis is impaired, and the introduction of glucagon may be ineffective. A side effect of glucagon administration may be vomiting, which creates a risk of aspiration. It is desirable for the patient's relatives to own the technique of glucagon injection.
Forecast
Mild hypoglycemia in trained patients against the background of good compensation of the disease is safe. Frequent hypoglycemia is a sign of poor compensation for diabetes; in most cases, in such patients, more or less pronounced hyperglycemia and a high level of glycated hemoglobin are determined at the rest of the day. In elderly patients with late complications of diabetes, hypoglycemia can provoke such vascular complications as myocardial infarction, stroke, hemorrhage in the retina. Hypoglycemic coma lasting up to 30 minutes with adequate treatment and rapid return of consciousness, as a rule, does not have any complications and consequences.
7.8. LATE COMPLICATIONS OF DIABETES MELLITUS
Late complications develop with both types of diabetes. Clinically, there are five main late complications of diabetes: macroangiopathy, nephropathy, retinopathy, neuropathy and diabetic foot syndrome. The non-specificity of late complications for certain types of diabetes is determined by the fact that their main pathogenetic link is chronic hyperglycemia. In this regard, at the time of manifestation of TD-1, late complications in patients almost never occur, developing through years and decades, depending on the effectiveness of the therapy. The greatest clinical significance in DM-1, as a rule, acquires diabetic microangiopathy (nephropathy, retinopathy) and neuropathy (diabetic foot syndrome). With DM-2, on the contrary, late complications are often detected already at the time of diagnosis. First, this is due to the fact that T2D manifests itself long before the diagnosis is established. Secondly, atherosclerosis, clinically manifested by macroangiopathy, has many links in common with diabetes of pathogenesis. With TD-2, the greatest clinical significance, as a rule, acquires diabetic macroangiopathy, which at the time of diagnosis is detected in the vast majority of patients. In each case, the set and severity of individual late complications vary from their paradoxical complete absence, despite the significant duration of the disease up to a combination of all possible variants in severe form.
Late complications are the leading cause of death in patients with diabetes, and given its prevalence, it is the most important medical and social health problem in most countries. In this regard, the main goal of treatment and observation of patients with diabetes is the prevention (primary, secondary, tertiary) of its late complications.
7.8.1. Diabetic macroangiopathy
Diabetic macroangiopathy is a collective concept that unites atherosclerotic lesions of large arteries in diabetes,
clinically manifested by coronary heart disease (CHD), obliterating atherosclerosis of the vessels of the brain, lower extremities, internal organs and arterial hypertension (Table 7.16).
Table. 7.16. Diabetic macroangiopathy
Etiology and pathogenesis
Probably similar to the etiology and pathogenesis of atherosclerosis in persons without diabetes. Atherosclerotic plaques do not differ in microscopic structure in persons with and without diabetes. Nevertheless, with diabetes, additional risk factors may come to the fore, or diabetes exacerbates known non-specific factors. These in diabetes include:
1. Hyperglycemia. It is a risk factor for atherosclerosis. A 1% increase in HbA1c levels in patients with T2DM increases
There is a 15% risk of myocardial infarction. The mechanism of atherogenic action of hyperglycemia is not entirely clear, perhaps it is associated with glycosing of the final products of LDL metabolism and collagen of the vascular wall.
2. Arterial hypertension (AH). In pathogenesis, great importance is attached to the renal component (diabetic nephropathy). Hypertension in TD-2 is no less significant risk factor for heart attack and stroke than hyperglycemia.
3. Dyslipidemia. Hyperinsulinemia, which is an integral component of insulin resistance in TD-2, causes a decrease in HDL levels, an increase in triglyceride levels and a decrease in density, i.e. an increase in LDL atherogenicity.
4. Obesity, which affects most patients with T2DM, is an independent risk factor for atherosclerosis, myocardial infarction and stroke (see paragraph 11.2).
5. Insulin resistance. Hyperinsulinemia and high levels of insulin-proinsulin-like molecules increase the risk of atherosclerosis, which may be associated with endothelial dysfunction.
6. Violation of blood coagulation. In diabetes, an increase in the level of fibrinogen, a platelet inhibitor activator and von Willebrand factor is determined, as a result of which a prothrombotic state of the blood coagulation system is formed.
7. Endothelial dysfunction, characterized by increased expression of the plasminogen inhibitor activator and cell adhesion molecules.
8. Oxidative stress leading to an increase in the concentration of oxidized LDL and F2 isoprostanes.
9. Systemic inflammation, in which there is an increase in the expression of fibrinogen and C-reactive protein.
The most significant risk factors for the development of coronary artery disease in TS-2 are elevated LDL, low HDL, arterial hypertension, hyperglycemia and smoking. One of the differences between the atherosclerotic process in diabetes is the more common and distal nature of the occlusive lesion, i.e. Relatively smaller arteries are more often involved in the process, which complicates surgical treatment and worsens the prognosis.
Epidemiology
The risk of developing CORD in people with TD-2 is 6 times higher than in people without diabetes, while it is the same for men and women. Arterial hypertension is detected in 20% of patients with TD-1 and in 75% with DM-2. In general, in patients with diabetes, it occurs 2 times more often than in persons without it. Obliterating atherosclerosis of peripheral vessels develops in 10% of patients with diabetes. Thromboembolism of cerebral vessels develops in 8% of patients with diabetes (2-4 times more often than in persons without diabetes).
Clinical manifestations
Basically, they do not differ from those in persons without diabetes. In the clinical picture of DM-2, macrovascular complications (myocardial infarction, stroke, occlusive damage to the vessels of the legs) often come to the fore, and it is during their development that hyperglycemia is often first detected in the patient. Perhaps, due to concomitant autonomic neuropathy, up to 30% of myocardial infarctions in persons with diabetes occur without a typical anginal attack (painless heart attack).
Diagnostics
The principles of diagnosis of complications of atherosclerosis (coronary artery disease, impaired cerebral circulation, occlusive damage to the arteries of the legs) do not differ from those for persons without diabetes. Measurement of blood pressure (BP) should be carried out at each visit of a patient with diabetes to the doctor, and the determination of the indicators of the lipid spectrum of the blood (total cholesterol, triglycerides, LDL, HDL) in diabetes should be carried out at least once a year.
Differential diagnostics
Other cardiovascular diseases, symptomatic arterial hypertension, secondary dyslipidemia.
Treatment
♦ Blood pressure control. The proper level of systolic blood pressure in diabetes is less than 130 mmHg, and diastolic 80 mmHg (Table 7.3). Most patients need to prescribe several antihypertensive drugs to achieve this goal. The drugs of choice of antihypertensive therapy for diabetes are ACE inhibitors and angiotensin receptor blockers, which, if necessary, are supplemented with thiazide diuretics. The drugs of choice for patients with diabetes who have had myocardial infarction are β-blockers.
♦ Correction of dyslipidemia. Target levels of indicators of the lipid spectrum are presented in Table. 7.3. The drugs of choice of lipid-lowering therapy are inhibitors of 3-hydroxy-3-methylglu-taryl-CoA reductase (statins).
♦ Antiplatelet therapy. Aspirin therapy (75-100 mg / day) is indicated for patients with diabetes older than 40 years with an increased risk of developing cardiovascular pathology (burdened family history, arterial hypertension, smoking, dyslipidemia, microalbuminuria), as well as all patients with clinical manifestations of atherosclerosis as a secondary prevention.
♦ Screening and treatment of coronary artery disease. Stress tests to exclude coronary artery disease are indicated for patients with symptoms of cardiovascular diseases, as well as in the detection of pathology in the ECG.
Forecast
75% of patients with TD-2 and 35% of patients with TD-1 die from cardiovascular diseases. Approximately 50% of patients with TD-2 die from complications of coronary artery disease, 15% from thromboembolism of cerebral vessels. Mortality from myocardial infarction in persons with diabetes exceeds 50%.
7.8.2. Diabetic retinopathy
Diabetic retinopathy (DR) is a microangiopathy of the retinal vessels, characterized by the development of microaneurysms, hemorrhages, exudative changes and proliferation of newly formed vessels, leading to partial or complete loss of vision (Table 7.17).
Aetiology
The main etiological factor in the development of DR is chronic hyperglycemia. Other factors (arterial hypertension, dyslipidemia, smoking, pregnancy, etc.) are of lesser importance.
Pathogenesis
The main links in the pathogenesis of DR are:
• microangiopathy of the retinal vessels, leading to narrowing of the lumen of the vessels with the development of hypoperfusion;
• degeneration of blood vessels with the formation of microaneurysms;
• progressive hypoxia, which stimulates the proliferation of blood vessels and leads to fatty degeneration and deposition of calcium salts in the retina;
Table. 7.17. Diabetic retinopathy
•
microinfarctions with exudation, leading to the formation of soft "cotton spots";
• deposition of lipids with the formation of dense exudates;
• proliferation of proliferating vessels in the retina with the formation of shunts and aneurysms, leading to dilatation of veins and aggravation of retinal hypoperfusion;
• the phenomenon of theft with further progression of ischemic, which is the cause of the formation of infiltrates and scars;
• retinal detachment as a result of its ischemic disintegration and the formation of vitreoretinal tractions;
• hemorrhages in the vitreous body as a result of hemorrhagic infarctions, massive vascular invasion and rupture of aneurysms;
• proliferation of iris vessels (diabetic rubeosis), leading to the development of secondary glaucoma;
• maculopathy with retinal edema.
Epidemiology
DR is the most common cause of blindness among the able-bodied population of developed countries, and the risk of developing blindness in patients with diabetes is 10-20 times higher than in the general population. At the time of diagnosis, DM-1 DR is not detected in almost any of the patients, after 5 years, the disease is detected in 8% of patients, and with thirty years of diabetes experience - in 98% of patients. At the time of diagnosis, DM-2 is detected in 20-40% of patients, and among patients with fifteen years of experience, DM-2 - in 85%. With DM-1, proliferative retinopathy is relatively more common, and with DM-2 - maculopathy (75% of cases of maculopathy).
Clinical manifestations
According to the generally accepted classification, there are 3 stages of DR
(table 7.18).
Diagnostics
A complete ophthalmological examination, including direct ophthalmoscopy with retinal photography, is indicated for patients with DM-1 3-5 years after the manifestation of the disease, and for patients with T-2 diabetes - immediately after its detection. In the future, such studies must be repeated annually.
Table. 7.18. Classification of diabetic retinopathy
Differential diagnostics
Other eye diseases in patients with diabetes.
Treatment
The basic principle of treatment of diabetic retinopathy, as well as other late complications, is the optimal compensation of diabetes. The most effective method of treating diabetic retinopathy and preventing blindness is laser photocoagulation. To
Rice. 7.11. Diabetic retinopathy:
(a) non-proliferative; b) preproliferative; c) proliferative
laser photocoagulation is the cessation of the functioning of newly formed vessels, which pose the main threat to the development of such serious complications as hemophthalmos, traction retinal detachment, iris rubeosis and secondary glaucoma.
Forecast
Blindness is recorded in 2% of patients with diabetes (3-4% of patients with DM-1 and 1.5-2% of patients with DIABET-2). The estimated incidence of new cases of blindness associated with DR is 3.3 cases per 100,000 population per year. With DM-1, a decrease in HbA1c to 7.0% leads to a 75% reduction in the risk of DEVELOPing DR and a 60% reduction in the risk of PROGRESSion of DR. With DM-2, a 1% reduction in HbA1c leads to a 20% reduction in the risk of developing DR.
7.8.3. Diabetic nephropathy
Diabetic nephropathy (DNF) is defined as albuminuria (more than 300 mg of albumin per day or proteinuria more than 0.5 g of protein per day) and / or a decrease in the filtration function of the kidneys in persons with diabetes in the absence of urinary infections, heart failure or other kidney disease. Microalbuminuria is defined as albumin excretion of 30-300 mg/day or 20-200 μg/min.
Etiology and pathogenesis
The main risk factors for DNF are the duration of diabetes, chronic hyperglycemia, arterial hypertension, dyslipidemia, kidney disease in parents. With DNF, the glomerular apparatus of the kidney is primarily affected.
1. One of the possible mechanisms by which hyperglycemia contributes to the development of glomerular lesions is the accumulation of sorbitol by activating the polyol pathway of glucose metabolism, as well as a number of glycation end products.
2. Hemodynamic disorders, namely intraglomerular arterial hypertension (increased blood pressure inside the glomeruli of the kidney) is the most important component of the pathogenesis
DNF.
The cause of intragrabal hypertension is a violation of the tone of the arterioles: the expansion of the bringing and the narrowing of the carrying.
Table. 7.19. Diabetic nephropathy
This, in turn, occurs under the influence of a number of humoral factors, such as angiotensin-2 and endothelin, as well as due to a violation of the electrolyte properties of the basement membrane of the glomeruli. In addition, intragrabal hypertension contributes to systemic hypertension, which is determined in most patients with DNP. Due to intraglomerular hypertension, damage to the basement membranes and filtration pores occurs,
through which trace (microalbuminuria) and then significant amounts of albumin (proteinuria) begin to penetrate. Thickening of the basement membranes causes a change in their electrolyte properties, which in itself leads to the ingress of more albumin into the ultrafiltrate even in the absence of a change in the size of the filtration pores.
3. Genetic predisposition. In relatives of patients with DNF, arterial hypertension occurs with an increased frequency. There is evidence of the relationship of DNP with polymorphism of the ACE gene. Microscopically, DNF reveals a thickening of the basement membranes of the glomeruli, the expansion of mesangium, as well as fibrous changes in the bringing and carrying arterioles. At the final stage, which clinically corresponds to chronic renal failure (CRF), focal (Kimmelstyle-Wilson), and then diffuse glomerulosclerosis, is determined.
Epidemiology
Microalbuminuria is determined in 6-60% of patients with TD-1 5-15 years after its manifestation. DNP is determined in 35% with DM-1, more often in men and in persons who developed TD-1 at the age of 15 years. With CD-2, DNP develops in 25% of the European race and 50% of the Asian race. The overall prevalence of DNP in DM-2 is 4-30%.
Clinical manifestations
A relatively early clinical manifestation, which is indirectly associated with DNP, is arterial hypertension. Other clinically obvious manifestations are late. These include manifestations of nephrotic syndrome and chronic renal failure.
Diagnostics
Screening for DNF in persons with diabetes involves annual testing for microalbuminuria in DM-1 5 years after the manifestation of the disease, and in DM-2 - immediately after its detection. In addition, at least an annual determination of the creatinine level is necessary to calculate the glomerular filtration rate (GFR). SCF can be calculated using various formulas, for example, according to the Cockcroft-Gault formula:
For men: a = 1.23 (the norm of GFR 100 - 150 ml / min) For women: a = 1.05 (the norm of GFR 85 - 130 ml / min)
In the initial stages of DNF, an increase in GFR can be detected, which gradually decreases as CRF develops. Microalbuminuria begins to be determined 5-15 years after the manifestation of T-1 diabetes; with DM-2 in 8-10% of cases, it is detected immediately after its detection, probably due to a prolonged asymptomatic course of the disease before diagnosis. The peak of the development of obvious proteinuria or albuminuria in TD-1 occurs between 15 and 20 years after its onset. Proteinuria indicates the irreversibility of DNP, which sooner or later will lead to chronic renal failure. Uremia on average develops 7-10 years after the appearance of obvious proteinuria. It should be noted that GFR does not correlate with proteinuria.
Differential diagnostics
Other causes of proteinuria and kidney failure in individuals with diabetes. In most cases, DNF is combined with arterial hypertension, diabetic retinopathy or neuropathy, in the absence of which differential diagnosis should be especially careful. In 10% of cases with TD-1 and in 30% of cases with CD-2, proteinuria is not associated with DNF.
Treatment
♦ The main conditions for primary and secondary prevention
DNF are the compensation of diabetes and the maintenance of normal systemic blood pressure. In addition, the primary prevention of DNF involves a decrease in the consumption of protein foods - less than 35% of the daily calorie intake.
♦ At the stages of microalbuminuria and proteinuria, patients are shown the appointment of ACE inhibitors or angiotensin receptor blockers. With concomitant arterial hypertension, they are prescribed in antihypertensive doses, if necessary, in combination with other antihypertensive drugs. With normal blood pressure, these drugs are prescribed in doses that do not lead to the development of hypotension. Both ACE inhibitors (with CD-1 and CD-2) and angiotensin receptor blockers (with CD-2) help prevent the transition of microalbuminuria to proteinuria. In some cases, against the background of this therapy in combination with compensation for diabetes in other parameters, microalbuminuria is eliminated. In addition, starting from the stage of microalbuminuria, it is necessary
reducing protein intake of less than 10% of daily calories (or less than 0.8 grams per kg of body weight) and salt of less than 3 grams per day.
♦ At the stage of crF, as a rule, correction of hypoglycemic therapy is required. Most patients with TS-2 should be transferred to insulin therapy, since cumulation of TSP carries a risk of developing severe hypoglycemia. In most patients with TD-1, there is a decrease in the need for insulin, since the kidney is one of the main places of its metabolism. With an increase in serum creatinine levels to 500 μmol / l or more, it is necessary to raise the question of preparing the patient for extracorporeal (hemodialysis, peritoneal dialysis) or surgical (kidney transplantation) method of treatment. Kidney transplantation is indicated at a creatinine level of up to 600-700 μmol / l and a decrease in the glomerular filtration rate of less than 25 ml / min, hemodialysis - 1000-1200 μmol / l and less than 10 ml / min, respectively.
Forecast
In 50% of patients with TD-1 and 10% with T2DM, who have proteinuria, develop CRF over the next 10 years. 15% of all deaths of patients with TS-1 younger than 50 years are associated with CRF due to DNF.
7.8.4. Diabetic neuropathy
Diabetic neuropathy (DNE) is a combination of syndromes of damage to the nervous system, which can be classified depending on the predominant involvement in the process of its various departments (sensorimotor, autonomic), as well as the prevalence and severity of the lesion (Table 7.20).
I. Sensorimotor neuropathy:
- symmetrical;
- focal (mononeuropathy) or polyfocal (cranial, proximal motor, mononeuropathy of the limbs and trunk).
II. Autonomous (autonomic) neuropathy:
- cardiovascular (orthostatic hypotension, cardiac denervation syndrome);
- gastrointestinal (gastric atony, biliary dyskinesia, diabetic enteropathy);
- urogenital (with impaired bladder function and sexual function);
- violation of the patient's ability to recognize hypoglycemia;
- violation of pupil function;
- violation of the functions of the sweat glands (distal anhidrosis, hyperhidrosis when eating).
Table. 7.20. Diabetic neuropathy
Etiology and pathogenesis
The main cause of DN is hyperglycemia. Several mechanisms of its pathogenesis are assumed:
• activation of the polyol pathway of glucose metabolism, as a result of which the accumulation of sorbitol, fructose and a decrease in the content of myoinositol and glutathione occurs in nerve cells. This, in turn, leads to the activation of free radical processes and a decrease in the level of nitric oxide;
• non-enzymatic glycosylation of membrane and cytoplasmic proteins of nerve cells;
• microangiopathy vasa nervorum, which leads to a slowdown in capillary blood flow and hypoxia of the nerves.
Epidemiology
The prevalence of DAY in both types of diabetes is about 30%. With DM-1, after 5 years from the onset of the disease, it begins to be detected in 10% of patients. The frequency of new cases of DNE in DM-2 is about 6% of patients per year. The most common option is distal symmetrical sensorimotor DNE.
Clinical manifestations
Sensorimotor DNE is manifested by a complex of motor and sensory disorders. A frequent symptom of the distal form of DNE is paresthesia, which is manifested by a feeling of "crawling goosebumps", numbness. Patients often complain of chilly legs, although they remain warm to the touch, which is a sign that distinguishes polyneuropathy from ischemic changes when the feet are cold to the touch. An early manifestation of sensory neuropathy is a violation of vibrational sensitivity. Characteristic is the syndrome of "restless legs", which is a combination of nocturnal paresthesia and hypersensitivity. Pain in the legs is more often disturbed at night, while sometimes the patient can not tolerate the touch of the blanket. In a typical case, pain in contrast to that of obliterating diseases of the arteries may decrease when walking. Years later, the pain can spontaneously stop due to the death of small nerve fibers responsible for pain sensitivity. Hypoesthesia is manifested by loss of sensitivity by the type of "stockings" and "gloves". Violation of deep, proprioceptive sensitivity leads to impaired coordination and difficulty moving (sensory ataxia). The patient complains of "other people's feet", a feeling of "standing on cotton wool". Violation of trophic innervation leads to degenerative changes in the skin, bones and tendons. Violation of pain sensitivity leads to frequent, unnoticed by the patient microtrauma of the feet, which are easily infected. Violation of coordination and walking leads to a non-physiological redistribution of the load on the joints of the foot. As a result, the anatomical relationships in the musculoskeletal system of the leg are disturbed.
The arch of the foot is deformed, swelling, fractures, chronic purulent processes develop (see paragraph 7.8.5).
There are several forms of autonomous DN. The cause of the cardiovascular form is a violation of the innervation of the cardiopulmonary complex and large vessels. The vagus nerve is the longest nerve, and therefore it is affected earlier than others. As a result of the predominance of sympathetic influences, rest tachycardia develops. An inadequate reaction to orthostasis is manifested by orthostatic hypotension and syncopal conditions. Vegetative denervation of the pulmonary-cardiac complex leads to the absence of heart rate variability. Autonomic neuropathy is associated with an increased prevalence of painless myocardial infarctions among patients with diabetes.
Symptoms of the gastrointestinal form of DNE are gastroparesis with delayed or, conversely, rapid emptying of the stomach, which can create difficulties in the selection of insulin therapy, since the time and volume of carbohydrate absorption varies indefinitely; esophageal atony, reflux esophagitis, dysphagia; watery diarrhea. The urogenital form of the DNE is characterized by atony of the ureters and bladder, leading to a tendency to urinary infections; erectile dysfunction (about 50% of patients with diabetes); retrograde ejaculation.
Other possible manifestations of vegetative DNA are impaired ability to recognize hypoglycemia, impaired pupil function, impaired function of the sweat glands (anhidrosis), diabetic amyotrophy.
Diagnostics
Neurological examination of patients with diabetes should be carried out annually. At a minimum, it involves conducting tests aimed at detecting distal sensorimotor neuropathy. To do this, an assessment of vibration sensitivity using a graduated tuning fork, tactile sensitivity using a monofilament, as well as temperature and pain sensitivity is used. According to the indications, the state of the autonomic nervous system is studied: a number of functional tests are used to diagnose the insufficiency of the parasympathetic innervation of the heart, such as measuring heart rate during deep breathing with an assessment of variability
heart rate and Valsalva test; an orthostatic test is used to diagnose the insufficiency of the sympathetic innervation of the heart.
Differential diagnostics
Neuropathy of another genesis (alcoholic, uremic, with
B12-deficient
anemia, etc.). The diagnosis of dysfunction of an organ as a result of autonomic neuropathy is established only after the exclusion of organ pathology.
Treatment
1. Optimization of hypoglycemic therapy.
2. Foot care (see paragraph 7.8.5).
3. The effectiveness of neurotropic drugs (α-lipoic acid) is not confirmed in all studies.
4. Symptomatic therapy (anesthesia, sildenafil for erectile dysfunction, fludrocortisone for orthostatic hypotension, etc.).
Forecast
In the initial stages, the DNE may be reversible against the background of persistent compensation for diabetes. DNE is determined in 80% of patients with ulcerative lesions and is the main risk factor for leg amputation
with diabetes.
7.8.5. Diabetic foot syndrome
Diabetic foot syndrome (SDS) is a pathological condition of the foot in diabetes, which occurs against the background of damage to peripheral nerves, skin and soft tissues, bones and joints and is manifested by acute and chronic ulcers, osteoarticular lesions and purulent necrotic processes (Table 7.21).
Etiology and pathogenesis
The pathogenesis of SDS is multicomponent and is represented by a combination of neuropathic and perfusion disorders with a pronounced tendency to infection. Based on the predominance in the pathogenesis of one or another of the listed factors, 3 main forms are distinguished.
VTS:
Table. 7.21. Diabetic foot syndrome
I. Neuropathic form (60-70%):
- without osteoarthropathy;
- with diabetic osteoarthropathy.
II. Neuroischemic (mixed) form (15-20%).
III. Ischemic form (3-7%).
Neuropathic form of SDS. In diabetic neuropathy, the distal parts of the longest nerves are primarily affected. Prolonged deficiency of trophic impulses leads to hypotrophy of the skin, bones, ligaments, tendons and muscles. The result of hypotrophy of connective structures is a deformation of the foot with a non-physiological redistribution of the support load and its excessive increase in individual areas. In these places, for example, in the projection area of the heads of the metatarsal bones, thickening of the skin and the formation of hyperkeratosis are noted. Constant pressure on these areas leads to inflammatory autolysis of the underlying soft tissues, which creates the prerequisites for the formation of an ulcerative defect. As a result of atrophy and impaired sweating, the skin becomes dry, easily cracked. Due to a decrease in pain sensitivity, the patient often does not pay attention to the changes that occur. He can not timely detect the inconvenience of shoes, which leads to the formation of scuffs and calluses, does not notice the introduction of foreign bodies, small wounds in the places of cracking. The situation is aggravated by a violation of deep sensitivity, manifested in a violation of gait, improper installation of the leg. Most often, the ulcerative defect is infected with staphylococci, streptococci, bacteria of the intestinal group; anaerobic flora is often joined. Neuropathic osteoarthropathy is the result of pronounced dystrophic changes in the bone-articular apparatus of the foot (osteoporosis, osteolysis, hyperostosis).
The ischemic form of SDS is a consequence of atherosclerosis of the arteries of the lower extremities, leading to a violation of the main blood flow, i.e. is one of the variants of diabetic macroangiopathy.
Epidemiology
SDS is observed in 10-25%, and according to some sources, in one form or another in 30-80% of patients with diabetes. In the United States, the annual cost of treating patients with diabetes with SDS is $ 1 billion.
Clinical manifestations
In the neuropathic form of SDS, the two most common types of lesions are distinguished: neuropathic ulcer and osteoarthropathy (with the development of
Rice. 7.12. Neuropathic ulcer in diabetic foot syndrome
Rice. 7.13. Charcot joint in diabetic foot syndrome
Charcot's joint). Neuropathic ulcers are usually localized in the sole and interdigital spaces, i.e. in the areas of the foot experiencing the greatest pressure (Fig. 7.12).
Destructive changes in the bone-ligamentous apparatus of the foot can progress for many months and lead to severe bone deformity - diabetic osteoarthropathy and the formation of the Charcot joint, while the foot is figuratively compared with a "bag of bones"
(figure 7.13).
With ischemic form of SDS
the skin on the feet is cold, pale or cyanotic; less often it has a pinkish-red tint due to the expansion of surface capillaries in response to ischemia. Ulcerative defects occur by the type of acral necrosis - on the tips of the fingers, the marginal surface of the heels (Fig. 7.14).
The pulse on the arteries of the foot, popliteal and femoral arteries is weakened or not palpated.
В типичных случаях пациенты предъявляют жалобы на «перемежающуюся хромоту». Тяжесть ишемического поражения конечности определяется тремя основными факторами: тяжестью стеноза, развитием коллатерального кровотока, состоянием свертывающей системы крови.
Диагностика
Осмотр ног больного СД должен производиться каждый раз во время визита к врачу, не реже раза в полгода. Диагностика СДС включает:
Rice. 7.14. Acral necrosis in the ischemic form of diabetic foot syndrome
• examination of the legs;
• assessment of neurological status - various types of sensitivity, tendon reflexes, electromyography;
• assessment of the state of arterial blood flow - angiography, dopplerometry, dopplerography;
• radiography of the feet and ankle joints;
• bacteriological examination of wound discharge.
Differential diagnostics
It is carried out with wound processes on the feet of another genesis, as well as other occlusive diseases of the vessels of the lower extremities and pathology of the joints of the foot. In addition, it is necessary to differentiate the clinical forms of SDS (Table 7.22).
Treatment
Treatment of a neuropathically infected form of SDS includes a set of the following measures:
- optimization of diabetes compensation, as a rule, an increase in the dose of insulin, and with TD-2 - a transfer to it;
- systemic antibiotic therapy;
- complete unloading of the foot (this can lead to the healing of ulcers that have existed for years within a few weeks);
- local treatment of the wound with the removal of areas of hyperkeratosis;
- foot care, proper selection and wearing of special shoes. Timely conservative therapy allows
avoid surgery in 95% of cases.
Table. 7.22. Differential diagnosis of clinical forms of SDS
Treatment of ischemic form of SDS includes:
• optimization of compensation for diabetes, as a rule, an increase in the dose of insulin, and with TD-2 - a transfer to it;
• in the absence of ulcerative-necrotic lesions, ergotherapy (1-2-hour walking per day, contributing to the development of collateral blood flow);
• revascularization operations on the affected vessels;
• conservative therapy: anticoagulants, aspirin (up to 100 mg / day), if necessary - fibrinolytics, prostaglandin E1 and prostacyclin preparations.
With the development of extensive purulent-necrotic lesions in all variants of SDS, the question of amputation is raised.
Forecast
From 50 to 70% of the total number of leg amputations performed falls on the share of patients with diabetes. Amputation of the legs in patients with diabetes is performed 20-40 times more often than in persons without diabetes.
7.9. DIABETES MELLITUS AND PREGNANCY
Gestational diabetes mellitus (GDM) is a violation of glucose tolerance first identified during pregnancy (Table 7.23). This definition does not exclude the fact that the pathology of carbohydrate metabolism could precede the onset of pregnancy. GDM should be distinguished from situations where a woman with previously diagnosed diabetes (due to age, more often TD-1) becomes pregnant.
Etiology and pathogenesis
GDD is similar to that of SD-2. High levels of ovarian and placental steroids, as well as an increase in the formation of cortisol by the adrenal cortex, lead to the development of physiological insulin resistance during pregnancy. The development of GDM is associated with the fact that insulin resistance, which naturally develops during pregnancy, and, consequently, the increased need for insulin in predisposed individuals exceeds the functional ability of β cells of the pancreas. After childbirth with the return of hormonal and metabolic relationships to the baseline level, it usually passes.
Table. 7.23. Gestational diabetes mellitus
GDM usually develops in the middle of the 2nd trimester, between 4 and 8 months of pregnancy. The vast majority of patients have excess body weight and a history of TD-2. Risk factors for the development of GDM, as well as groups of women with a low risk of developing GDM, are given in Table. 7.24.
Table. 7.24. Risk factors for gestational diabetes mellitus
Hyperglycemia of the mother leads to hyperglycemia in the circulatory system of the child. Glucose easily penetrates the placenta and continuously passes to the fetus from the mother's blood. Active transport of amino acids and transfer of ketone bodies to the fetus also occur. In contrast, insulin, glucagon and free fatty acids of the mother do not enter the blood of the fetus. In the first 9-12 weeks of pregnancy, the pancreas of the fetus does not yet produce its own insulin. This time corresponds to the phase of fetal organogenesis, when, with constant hyperglycemia, various malformations (heart, spine, spinal cord, gastrointestinal tract) can form in the mother. From the 12th week of pregnancy, the fetal pancreas begins to synthesize insulin, and in response to hyperglycemia, reactive hypertrophy and hyperplasia of the β cells of the fetal pancreas develop. Due to hyperinsulinemia, fetal macrosomia develop, as well as inhibition of lecithin synthesis, which explains the high incidence of respiratory distressindrome in newborns. As a result of hyperplasia of β cells and hyperinsulinemia, a tendency to severe and prolonged hypoglycemia appears.
Epidemiology
Diabetes affects 0.3% of all women of reproductive age, 0.2-0.3% of pregnant women are already initially sick with diabetes, and in 1-14% of pregnancies GDM develops or manifests true diabetes. The prevalence of GDM varies in different populations, for example, in the United States it is detected in about 4% of pregnant women (135 thousand cases per year).
Clinical manifestations
With GSD, there are none. There may be non-specific symptoms of decompensation of diabetes.
Diagnostics
Determination of fasting blood glucose levels is indicated for all pregnant women as part of a biochemical blood test. Women who are at risk (Table 7.24) are shown an oral glucose tolerance test (OGTT). Many options for its implementation in pregnant women are described. The simplest of them implies the following rules:
• 3 days before the examination, the woman is on a regular diet and adheres to her usual physical activity;
• the test is carried out in the morning on an empty stomach, after a night fast for at least 8 hours;
• after taking a blood sample on an empty stomach, a woman drinks a solution consisting of 75 grams of dry glucose dissolved in 250-300 ml of water for 5 minutes; re-determination of the level of glycemia is carried out after 2 hours.
• the diagnosis of GDM is established according to the following criteria:
- whole blood glucose (venous, capillary) on an empty stomach > 6.1 mmol / l or
- venous blood plasma glucose ≥ 7 mmol / l or
- glucose of whole capillary blood or venous blood plasma 2 hours after loading 75 g of glucose ≥ 7.8 mmol / l.
• if a woman who belongs to the risk group, the results of the study correspond to the norm, the test is repeated at 24-28 weeks of pregnancy.
Differential diagnostics
GSD and true SD; glucosuria of pregnant women.
Treatment
The risk to the mother and fetus, as well as approaches to the treatment of diabetes and the features of its control in GDM and in true diabetes are the same. Late complications of diabetes during pregnancy can progress significantly, but with high-quality compensation for diabetes, there are no indications for abortion. A woman suffering from diabetes (as a rule, we are talking about TD-1), should plan a pregnancy at a young age, when the risk of complications is lowest. If pregnancy is planned, it is recommended to cancel the cont-
detection a few months after the optimal compensation has been achieved. Contraindications to pregnancy planning are severe nephropathy with progressive renal failure, severe coronary artery disease, severe proliferative retinopathy that cannot be corrected, ketoacidosis in early pregnancy (ketone bodies are teratogenic factors).
The goal of treating GDM and true diabetes during pregnancy is to achieve the following laboratory indicators:
• fasting glycemia < 5-5.8 mmol / l;
• glycemia 1 hour after eating < 7.8 mmol / l;
• glycemia 2 hours after eating < 6.7 mmol / l;
• the average value of the daily glycemic profile < 5.5 mmol / l;
• the level of HbA1c with monthly monitoring, as in healthy (4-6%).
With TD-1, as well as outside pregnancy, a woman should receive intensive insulin therapy, but the level of glycemia during pregnancy is recommended to be assessed 7-8 times a day. If it is impossible to achieve normoglycemic compensation against the background of conventional injections, it is necessary to consider transferring the patient to insulin therapy using an insulin dispenser.
At the first stage of treatment of GDM, diet therapy is prescribed, which consists in limiting the daily calorie to about 25 kcal / kg of actual weight, primarily due to easily digestible carbohydrates and animal fats, as well as the expansion of physical exertion. If, against the background of diet therapy, it is not possible to achieve the set goals of treatment, the patient should be prescribed intensive insulin therapy. Any tableted hypoglycemic drugs (TSP) during pregnancy are contraindicated. About 15% of women need to be transferred to insulin therapy.
Forecast
With unsatisfactory compensation for GDM and diabetes during pregnancy, the probability of developing various pathologies in the fetus is 30% (the risk is 12 times higher than in the general population). In more than 50% of women who had GDM during pregnancy, over the next 15 years, TD-2 manifests.
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