Diabetes mellitus type 2 is a chronic disease manifested by a violation of carbohydrate metabolism with the development of hyperglycemia due to insulin resistance and secretory dysfunction of beta 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, type 2 diabetes is sometimes called a cardiovascular disease.
Diabetes mellitus type 2 is a multifactorial disease with hereditary predisposition. Most patients with type 2 diabetes indicate the presence of type 2 diabetes in their immediate family; In the presence of type 2 diabetes mellitus, in one of the parents the probability of its development in the offspring during life is 40%. One gene, whose polymorphism determines predisposition to type 2 diabetes, has not been found. Great importance in the implementation of hereditary predisposition to type 2 diabetes mellitus is played by environmental factors, in the first place, the particular way of life. Risk factors for developing type 2 diabetes are:
- obesity, especially visceral;
- ethnicity (especially when changing the traditional way of life to the western one);
- type 2 diabetes in close relatives;
- sedentary lifestyle;
- features of the diet (high intake of refined carbohydrates and low fiber content);
- arterial hypertension.
Pathogenetically, type 2 diabetes mellitus is a heterogeneous group of metabolic disorders, which is what determines its significant clinical heterogeneity. At the heart of its pathogenesis is insulin resistance (reduction of insulin-mediated glucose utilization of tissues), which is realized against the background of secretory dysfunction of beta cells. Thus, there is a violation of the balance of sensitivity to insulin and insulin secretion. Secretory dysfunction of beta cells is to slow the “early” secretory release of insulin in response to an increase in blood glucose levels. In this case, the first (fast) phase of secretion, which consists in the emptying of vesicles with accumulated insulin, is virtually absent; 2nd (slow) The secretion phase is performed in response to stabilizing hyperglycemia constantly, in tonic mode, and despite the excessive secretion of insulin, the level of glycemia against insulin resistance is not normalized.
The consequence of hyperinsulinemia is a decrease in the sensitivity and number of insulin receptors, as well as suppression of 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% of streets with visceral obesity and by 80% – streets with type 2 diabetes mellitus. Due to the insulin resistance of hepatocytes and portal hyperinsulinemia hyperproduction of glucose by the liver occurs, and fasting hyperglycemia develops, which is detected in the majority of patients with type 2 diabetes, including in the early stages of the disease.
By itself, hyperglycemia adversely affects the nature and level of secretory activity of beta cells (glucose toxicity). Over the years and decades, the existing hyperglycemia ultimately leads to the depletion of insulin production by beta 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 sufficient to prevent ketoacidosis, with diabetes mellitus type 2 almost always persists.
The prevalence of type 2 diabetes varies in different countries and ethnic groups. With age, the incidence of type 2 diabetes is increasing: among adults, the prevalence of type 2 diabetes is 10%, among people over 65 years, it reaches 20%.
WHO predicts an increase in the number of diabetic patients in the world by 122% over the next 20 years (from 135 to 300 million). This is due both to the progressive aging of the population. In recent years there has been a significant “rejuvenation” of type 2 diabetes mellitus and an increase in its incidence among children.
In most cases, the expressed clinical manifestations are absent, and the diagnosis is established by routine determination of the level of glycemia. The disease usually manifests at the age of over 40, with the overwhelming majority of patients having obesity and other components of the metabolic syndrome. Patients do not complain of a decline in performance, if there are no other reasons for this. Complaints about thirst and polyuria rarely reach significant levels. Quite often, patients are concerned about skin and vaginal itching, so they turn to dermatologists and gynecologists. Since the actual manifestation of type 2 diabetes mellitus is often many years before the diagnosis is made (on average about 7 years), in many patients, the symptoms and manifestations of late complications of diabetes mellitus dominate the clinical picture at the time of the diagnosis. Moreover, the first treatment of a patient with type 2 diabetes mellitus for medical care very often occurs due to late complications. Thus, patients can be hospitalized in surgical hospitals with ulcerative foot injuries (diabetic foot syndrome), treated due to a progressive decrease in vision to ophthalmologists (diabetic retinopathy), hospitalized with heart attacks, strokes, obliterating lesions of the leg vessels to the institutions where they first discover hyperglycemia.
Diagnosis of type 2 diabetes in the vast majority of cases is based on the detection of hyperglycemia of streets with typical clinical signs of type 2 diabetes mellitus (obesity, age over 40-45, positive family history of type 2 diabetes mellitus, other components of the metabolic syndrome), in the absence of clinical and laboratory signs of absolute deficiency of insulin (expressed weight loss, ketosis). The combination of high prevalence of type 2 diabetes, its inherent long asymptomatic course and the possibility of preventing its severe complications under the condition of early diagnosis predetermine the need for screening, i.e. a survey to exclude type 2 diabetes mellitus among people without any symptoms of the disease. The main test, as indicated, is to determine the level of fasting glycemia. It is shown in the following situations:
- All people over the age of 45 years, especially with an excess of body weight (BMI more than 25 kg / m2) with an interval of every 3 years.
- 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;
- type 2 diabetes in close relatives;
- belonging to high risk nationalities of type 2 diabetes (African American, Hispanic, Native Americans, etc.);
- women who have given birth to a child weighing more than 4 kg and / or if there is a history of gestational diabetes mellitus;
- arterial hypertension (> 140/90 mm Hg);
- level of HDL> 0.9 mmol / L and / or triglycerides> 2.8 mmol / l;
- polycystic ovarian syndrome;
- impaired glucose tolerance and impaired fasting glycemia;
- cardiovascular diseases.
A significant increase in the incidence of type 2 diabetes among children dictates the need for screening of the level of glycemia in children and adolescents (from 10 years with an interval of 2 years or with the onset of puberty, if it occurred at an earlier age), belonging to high-risk groups, to which include children with excess body weight (BMI and / or body weight> 85 percentile age-appropriate, or weight more than 120% relative to ideal) in combination with any of the two listed additional risk factors:
- type 2 diabetes mellitus among relatives of the first or second line of relationship;
- belonging to high-risk nationalities;
- clinical manifestations associated with insulin resistance (acanthosis nigricans, arterial hypertension, dyslipidemia);
- diabetes mellitus, including gestational, in the mother.
The main components of the treatment of type 2 diabetes are: diet therapy, expansion of physical activity, sugar therapy, prevention and treatment of late complications of diabetes mellitus. Since most patients with type 2 diabetes are obese, the diet should be aimed at weight loss (hypocaloric) and prevention of late complications, primarily macroangiopathy (atherosclerosis). A hypokaloric diet is necessary for all patients with an excess of 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 content of food to 1000-1200 calories for women and 1200-1600 kcal for men. The recommended ratio of the main food components in type 2 diabetes is similar to that of type 1 diabetes (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, drinking alcohol on the background of therapy with drugs of sulfonylurea and insulin can provoke the development of hypoglycemia.
Recommendations for the expansion of physical activity should be individualized. In the beginning, aerobic loads (walking, swimming) of moderate intensity lasting 30-45 minutes 3-5 times a day (about 150 minutes per week) are recommended. In the future, it is necessary to gradually increase physical activity, which significantly contributes to the reduction and normalization of body weight. In addition, physical activity contributes to a decrease in insulin resistance and has a hypoglycemic effect.
Drugs for hypoglycemic therapy in type 2 diabetes 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 biguanide group. The main components of the mechanism of its action are:
- Suppression of gluconeogenesis in the liver (decreased glucose production by the liver), which leads to a decrease in fasting glycemia.
- Decreased insulin resistance (increased utilization of glucose by peripheral tissues, especially muscles).
- Activation of anaerobic glycolysis and a decrease in glucose absorption in the small intestine.
Metformin is the drug of the first choice of hypoglycemic therapy in patients with type 2 diabetes, obesity and fasting hyperglycaemia. Among the side effects are relatively common dyspepsia (diarrhea), which, as a rule, are transient and pass independently 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 does not develop (its action is designated as anti-hyperglycemic, and not as hypoglycemic). Contraindications to the appointment of metformin are pregnancy, severe cardiac, hepatic, renal and other organ failure, as well as hypoxic states of a different genesis. The extremely rare complication that occurs when metformin is administered without taking into account the above contraindications is lactatacidosis, which is a consequence of the hyperactivation of anaerobic glycolysis.
Thiazolidinediones (pioglitazone, rosiglitazone) are agonists of peroxisome proliferator-activated receptors (PPAR-y). Thiazolidinediones activate the metabolism of glucose and lipids in muscle and fatty tissues, which leads to an increase in the activity of endogenous insulin, i.e. To the elimination of insulin resistance (insulin sensitizers). Very effective combination of thiazolidinediones with metformin. 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 thiazolidinediones include fluid retention and swelling, which often develop with a combination of drugs with insulin.
II. Drugs that affect the beta-cell and promote increased secretion of insulin
This group includes preparations of the sulfonylurea of iglinide (prandial regulators of glycemia), which are used primarily to normalize the level of glycemia after eating. The main target of sulfonylurea drugs are beta cells of pancreatic islets. Sulfonylureas are bound to the beta-cell membrane with specific receptors. This leads to the closure of ATP-dependent potassium channels and the depolarization of the cell membrane, which in turn facilitates the opening of calcium channels. The intake of calcium inside the beta cells leads to their degranulation and the release of insulin into the blood. In clinical practice, a lot of sulfonylureas are used, which differ in the duration and severity of the hypoglycemic effect.
The main and quite frequent side effect of sulfonylureas is hypoglycemia. It can occur with an overdose of the drug, its cumulation (kidney failure), non-compliance with diet (skipping meals, drinking alcohol) or regimen (significant physical load, before which the dose of sulfonylureas is not reduced or carbohydrates taken).
The group of clays (prandial regulators of glycemia) include repaglinide (a benzoic acid derivative) and nateglinide (a derivative of D-phenylalanine). After taking the drugs, they quickly and reversibly interact with the sulfonylurea receptor on the beta-cell, resulting in a short increase in the level of insulin, which mimics the first phase of its secretion in normal. Drugs are taken 10-20 minutes before the main meals, usually 3 times a day.
III. Drugs that reduce glucose uptake in the intestine
This group includes acarbose and guar gum. The mechanism of action of acarbose is a reversible blockade of alpha-glycosidases of the small intestine, as a result of which the processes of sequential fermentation and absorption of carbohydrates are slowed down, the rate of resorption and the intake of glucose into the liver decrease and the level of postprandial glycemia decreases. 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 non-absorbed carbohydrates into the large intestine. The sugar-reducing effect of acarbose is very moderate.
In clinical practice, tableted hypoglycemic preparations are effectively combined with each other and with insulin preparations, since in most patients both fasting and postprandial hyperglycemia are determined simultaneously. There are numerous fixed combinations of drugs in one tablet. Most often, an aqueous tablet combines metformin with various preparations of sulfonylurea, as well as metformin, with styazolidine diones.
IV. Insulin and insulin analogues
At a certain stage, insulin preparations begin to receive up to 30-40% of patients with type 2 diabetes mellitus.
Indications for insulin therapy for type 2 diabetes mellitus:
- obvious signs of insulin deficiency, such as progressive weight loss and ketosis, severe hyperglycemia;
- large 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;
- the lack of a stable compensation, despite the appointment of maximum daily doses of various tableted hypoglycemic drugs;
- late stages of late complications of diabetes mellitus (severe polyneuropathy and retinopathy, chronic renal failure).
The most frequent variant of transferring patients with type 2 diabetes to insulin therapy is the administration of insulin for prolonged action in combination with the taken tableted, sugar-lowering medications. In a situation where the level of fasting glycemia can not be controlled by the appointment of metformin or the latter is contraindicated, the patient is given an evening (at night) injection of insulin. If it is impossible to control both tablet and post-prandial glycemia with tablet preparations, the patient is transferred to monoinsulin therapy. Usually, with type 2 diabetes, insulin therapy is carried out according to the so-called “traditional” scheme, which implies the appointment of fixed doses of long-acting insulin and short-acting. In this regard, standard insulin mixtures containing an aqueous vial of short (ultrashort) and prolonged-acting insulin are convenient. The choice of traditional insulin therapy is determined by the fact that in diabetes mellitus type 2, it is often prescribed for elderly patients, whose training of independent changes in insulin dose is difficult. In addition, intensive insulin therapy, whose goal is to maintain compensation for carbohydrate metabolism at a level approaching normoglycemia, carries an increased risk of hypoglycemia. If the lungs of hypoglycemia are not a serious hazard for young patients, in elderly patients with a reduced threshold of hypoglycemia, they can have very adverse effects on the part of the cardiovascular system. Young patients with type 2 diabetes mellitus, and also patients promising in terms of effective learning opportunities, can be assigned an intensive version of insulin therapy.
The main cause of disability and death of patients with type 2 diabetes is late complications, 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 HbAlc in patients with type 2 diabetes mellitus by 1% leads to a reduction in overall mortality by approximately 20%, by 2% and 3%, respectively by about 40% and 60%, respectively.