Type 2 diabetes mellitus (pathogenesis and treatment)

Type 2 diabetes mellitus (DM) was and remains the most important medical and social problem of our time, due to its widespread prevalence, as well as premature disability and death of patients suffering from this disease.
It is well known that premature disability and mortality in patients with type 2 diabetes are primarily associated with its macrovascular complications, namely with various manifestations of atherosclerosis (IHD, acute myocardial infarction, stroke, gangrene of the lower extremities, etc.).
Numerous studies have revealed a direct relationship between the degree of compensation of carbohydrate metabolism, the timing and progression rate of macro- and microvascular complications of type 2 diabetes. In this regard, the achievement of compensation for carbohydrate metabolism is an important link in a set of measures aimed at preventing the development or slowing of the progression of late complications this disease.
Type 2 diabetes is a heterogeneous disease. A prerequisite for its successful therapy is the impact on all known links of the pathogenesis of this disease.

Pathogenesis

Currently, the key links in the pathogenesis of type 2 diabetes are insulin resistance (IR), impaired insulin secretion, increased liver glucose production, as well as a hereditary predisposition and lifestyle and nutritional characteristics leading to obesity.
The role of heredity in the development of type 2 diabetes is not in doubt. Long-term studies have shown that in monozygotic twins, the concordance for type 2 diabetes is close to 100%. Hypodynamia and excessive nutrition lead to the development of obesity, thereby exacerbating the genetically determined IR and contributing to the realization of genetic defects that are directly responsible for the development of type 2 diabetes.
Obesity, especially visceral (central, android, abdominal), plays an important role in the pathogenesis of IR and associated metabolic disorders, and type 2 diabetes. This is due to the features of visceral adipocytes, which are characterized by a reduced sensitivity to antilipolytic action nsulina and increased sensitivity to the lipolytic action of catecholamines. In this regard, in the visceral adipose tissue, the lipolysis process is activated, which in turn leads to the entry of a large amount of free fatty acids (FFA) into the portal circulation, and then into the systemic circulation. In the liver, FFAs inhibit the binding of insulin to hepatocytes, which, on the one hand, contributes to systemic hyperinsulinemia, and on the other hand, exacerbates hepatocyte IR and inhibits the inhibitory effect of the hormone on hepatic gluconeogenesis (GNG) and glycogenolysis. The latter circumstance causes increased glucose production by the liver. A high concentration of FFA in the peripheral blood circulation aggravates skeletal muscle IR and interferes with the utilization of glucose by myocytes, which leads to hyperglycemia and compensatory hyperinsulinemia. Thus, a vicious circle is formed: an increase in the concentration of FFA leads to even greater IR at the level of adipose, muscle and liver tissue, hyperinsulinemia, activation of lipolysis, and an even greater increase in the concentration of FFA. Hypodynamia also exacerbates the existing IR, as the translocation of glucose transporters (GLUT-4) in muscle tissue at rest is sharply reduced.
Insulin resistance, which usually occurs with type 2 diabetes, is a condition characterized by an insufficient biological response of cells to insulin when it is sufficiently concentrated in the blood. Currently, IR is more associated with impaired insulin action at the postreceptor level, in particular with a significant decrease in the membrane concentration of specific glucose transporters (GLUT-4, GLUT-2, GLUT-1).
One of the most important consequences of IR is dyslipoproteinemia, hyperinsulinemia, arterial hypertension and hyperglycemia, which are currently considered as the main risk factors for the development of atherosclerosis.

Violation of insulin secretion in patients with type 2 diabetes is usually detected by the time the disease manifests itself. So, in patients, the first phase of insulin secretion was reduced during an intravenous glucose load, the secretory response to mixed food was delayed, the concentration of proinsulin and its metabolic products was increased, and the rhythm of fluctuations in insulin secretion was disturbed. It is possible that at an early stage of impaired glucose tolerance, a leading role in changing insulin secretion belongs to an increase in the concentration of FFA (the phenomenon of lipotoxicity). Further, the aggravation of insulin secretion disorders and the development of its relative deficiency over time occurs under the influence of hyperglycemia (the phenomenon of glucose toxicity). In addition, the compensatory abilities of b-cells in individuals with IR are often limited due to a genetic defect in glucokinase and / or glucose transporter GLUT-2, which are responsible for insulin secretion in response to glucose stimulation. Therefore, the achievement and maintenance of normoglycemia will not only slow down the development of late complications of type 2 diabetes, but also to some extent prevent the violation of insulin secretion.
Chronic increased liver glucose production is an early link in the pathogenesis of type 2 diabetes, leading in particular to fasting hyperglycemia. Excessive influx of free fatty acids (FFA) into the liver during visceral fat lipolysis stimulates GNH by increasing acetyl CoA production, suppressing glycogen synthase activity, and also excessive lactate formation. In addition, excess FFAs inhibit the uptake and internalization of insulin by hepatocytes, which exacerbates hepatocyte IR with all the ensuing consequences.
Thus, summarizing the above, at present, the pathogenesis of type 2 diabetes can be represented in the form of a scheme (Fig. 1).

Treatment

The selection of adequate complex therapy and the achievement of disease compensation in patients with type 2 diabetes presents significant difficulties. Most likely this is due to the significant heterogeneity of type 2 diabetes, which makes it difficult to select the optimal treatment from the pathogenetic point of view in each case.
To achieve compensation for type 2 diabetes, the prescribed therapy should maximally affect all known pathogenesis links of this disease.
First of all, patients should be trained in the principles of the treatment of type 2 diabetes, adhere to a low-calorie diet, possibly expand physical activity and have self-monitoring tools for flexible correction of sugar-lowering drugs.
However, in most cases, in spite of strict adherence to the diet, in order to compensate for the disease, it is necessary to prescribe medication sugar-lowering therapy.
Currently, in the treatment of patients with type 2 diabetes, a-glucosidase inhibitors, metformin, insulin secretion stimulating agents (sulfonylurea derivatives, benzoic acid derivatives), insulin are used.
A-glucosidase inhibitors are pseudotetrasaccharides (acarbose) and pseudomonosaccharides (miglitol). The mechanism of action of these drugs is as follows: competing with mono- and disaccharides for binding sites on digestive enzymes, they slow down the processes of sequential cleavage and absorption of carbohydrates throughout the small intestine, which leads to a decrease in the level of postprandial hyperglycemia and facilitates the achievement of carbohydrate metabolism compensation. In the form of monotherapy, a-glucosidase inhibitors are most effective for normal fasting glycemia and minor post-nutritional hyperglycemia, as well as in combination with other sugar-lowering drugs. The main side effect of a-glucosidase inhibitors is flatulence and diarrhea, and therefore they are contraindicated in patients with ulcerative colitis and hernias of various localization.
Sulfonylurea derivatives (PSM) are an indispensable link in the treatment of type 2 diabetes, as over time, insulin secretion by b-cells is impaired and its relative deficiency is observed in almost all patients with type 2 diabetes.

PSM second generation

The mechanism of action of PSM is associated with the ability of the latter to stimulate the secretion of endogenous insulin, especially in the presence of glucose. Preparations of this group have the ability to bind to specific receptors on the surface of b-cell membranes. The specified binding leads to the closure of ATP-dependent potassium channels and depolarization of the membranes of b-cells, which in turn contributes to the opening of calcium channels and the rapid entry of calcium into these cells. This process leads to degranulation and secretion of insulin, in connection with which its concentration in the blood and liver increases. This contributes to the utilization of glucose by hepatocytes and peripheral cells and a decrease in glycemia.
Currently, in the treatment of patients with type 2 diabetes, second-generation PSM are mainly used. Compared with PSM of the first generation, they have a 50-100 times more pronounced sugar-lowering effect, which allows them to be used in small doses.
The second generation PSM therapy should be started with minimal doses, gradually increasing the dose as necessary. In each case, the dose of the drug should be selected individually, bearing in mind the high risk of hypoglycemic conditions in the elderly.
Glibenclamide has a pronounced sugar-lowering effect, and therefore its appointment in the early stages of the disease can lead to hypoglycemic conditions. Micronized forms of glibenclamide (1.75 and 3.5 mg) have a high bioavailability and low risk of developing hypoglycemic conditions.
Glipizide also has a pronounced sugar-lowering effect. At the same time, this drug poses minimal danger in terms of hypoglycemic reactions. The indicated advantage of glipizide is due to the absence of a cumulative effect, since the metabolites formed during its inactivation in the liver do not have a hypoglycemic effect. Currently, a new prolonged GITS form of glipizide is used – glibenesis retard (glucotrol XL) (GITS – gastrointestinal therapeutic form), which ensures the optimal content of the drug in the blood with a single dose.
Glycvidone is a hypoglycemic drug, the appointment of which is possible in people with kidney disease. About 95% of the dose received is excreted through the gastrointestinal tract and only 5% through the kidneys. A multicenter study of the effect of glycidone on liver function has proved the possibility of its safe use in people with impaired function.
Gliclazide in addition to the hypoglycemic effect has a positive effect on microcirculation, hemostasis, some hematological parameters and rheological properties of blood, which is extremely important for patients with type 2 diabetes. The listed effects of glyclazide are due to its ability to reduce platelet aggregation, increasing their relative disaggregation index, and viscosity blood.
Glimepiride – a new PSM, unlike all of the above drugs, binds to another receptor on the b-cell membrane. The indicated quality of the drug is manifested in the form of its pharmacokinetics and pharmacodynamics. So, with a single use of glimepiride, its constant concentration in the blood is maintained, which is necessary to ensure a sugar-lowering effect for 24 hours. Features of the association of glimepiride with the receptor contribute to the rapid onset of a hypoglycemic effect, and dissociation with the same receptor practically eliminates the risk of hypoglycemic conditions.
Side effects when using PSM, as a rule, are observed in exceptional cases and are manifested by dyspeptic disorders, sensations of a metallic taste in the mouth, allergic reactions, leuko and thrombocytopenia, agranulocytosis. The listed undesirable consequences of the use of these drugs require a dose reduction or their complete abolition and are practically not observed when using PSM of the second generation.
Contraindications for the appointment of PSM are type 1 diabetes and all its acute complications, pregnancy and lactation, renal and hepatic failure, the addition of an acute infectious disease, extensive or abdominal surgery, a progressive decrease in the patient’s body weight with unsatisfactory indicators of carbohydrate metabolism, and acute macrovascular complications (heart attack myocardium, stroke, gangrene).
Biguanides began to be used in the treatment of patients with type 2 diabetes in the same years as PSM. However, due to the frequent cases of lactic acidosis when taking phenformin and buformin, guanidine derivatives were practically excluded from the treatment of type 2 diabetes patients. Metformin remained the only drug approved for use in many countries.
An analysis of the results of treatment of patients with type 2 diabetes in the last decade around the world showed that the appointment of PSM alone is usually not enough to achieve compensation for type 2 diabetes. Given this fact, metformin has again been widely used in the treatment of patients with type 2 diabetes . This circumstance was largely facilitated by the acquisition of new knowledge about the mechanism of action of this drug. In particular, studies in recent years have shown that the risk of a lethal increase in blood levels of lactic acid during long-term treatment with metformin is only 0.084 cases per 1000 patients per year, which is ten times lower than the risk of developing severe hypoglycemic conditions with PSM or insulin therapy. Compliance with contraindications to the appointment of metformin eliminates the risk of developing this side effect.
The mechanism of action of metformin is fundamentally different from that of PSM, and therefore can be successfully used both as monotherapy for type 2 diabetes, and in combination with the latter and insulin. The antihyperglycemic effect of metformin is primarily associated with a decrease in liver glucose production. The described action of metformin is due to its ability to suppress GNG by blocking the enzymes of this process in the liver, as well as FFA production and fat oxidation. An important link in the mechanism of action of metformin is its ability to reduce the IR available in type 2 diabetes. This effect of the drug is due to the ability of metformin to activate the insulin receptor tyrosine kinase and translocation of GLUT-4 and GLUT-1 in muscle cells, thereby stimulating muscle glucose utilization. In addition, metformin enhances anaerobic glycolysis in the small intestine, which slows down the process of glucose entering the blood after eating and reduces the level of postprandial hyperglycemia. In addition to the listed effect of metformin on carbohydrate metabolism, it should be emphasized that it has a positive effect on lipid metabolism, which is extremely important for type 2 diabetes. The positive effect of metformin on fibrinolytic properties of blood is also shown by suppressing the plasminogen-1 activator inhibitor, the level of which is significantly increased in type 2 diabetes .
Indications for the use of metformin is the inability to achieve a compensation of disease in patients with type 2 diabetes (especially obesity) on the background diet. The combination of metformin and PSM contributes to the achievement of better results for the treatment of type 2 diabetes. Improving the control of diabetes with the combination of metformin and PSM is due to the different types of effects of these drugs on the pathogenetic links of type 2 diabetes. Metformin administration to patients with type 2 diabetes receiving insulin therapy prevents weight gain.
The initial daily dose of metformin is usually 500 mg. If necessary, after a week from the start of therapy, provided there are no side effects, the dose of the drug can be increased. The maximum daily dose of metformin is 3000 mg. Take the drug with food.
Side effects of metformin include lactic acidosis, diarrhea and other dyspeptic symptoms, a metallic taste in the mouth, rarely nausea and anorexia, which usually quickly disappear with a decrease in dose. Persistent diarrhea is an indication for the abolition of metformin.
With long-term use of metformin in large doses, one should remember about the possibility of reducing the absorption of vitamins B12 and folic acid in the gastrointestinal tract, and if necessary, individually decide on the additional purpose of these vitamins.
Given the ability of metformin to enhance anaerobic glycolysis in the small intestine in combination with the suppression of GNH in the liver, blood lactate should be monitored at least 2 times a year. If there are complaints from the patient about muscle pain, you should immediately examine the level of lactate, and with an increase in the blood content of the latter or creatinine, treatment with metformin should be discontinued.
Contraindications to the appointment of metformin are impaired renal function (decreased creatinine clearance below 50 ml / min or increased creatinine in the blood above 1.5 mmol / l), since the drug is practically not metabolized in the body and excreted by the kidneys unchanged, as well as any hypoxic state nature (circulatory failure, respiratory failure, anemia, infections), alcohol abuse, pregnancy, lactation and an indication of a history of lactic acidosis.
If it is not possible to achieve compensation for diabetes while taking oral hypoglycemic drugs (PSPP), it is recommended that patients be transferred to the combined therapy of PSM and / or metformin and insulin, or to monotherapy with insulin. According to the duration of use and type of insulin therapy can be classified as follows.
Temporary short-term insulin therapy is usually prescribed for stressful situations (AMI, stroke, surgery, trauma, infection, inflammation, etc.) due to a sharp increase in the need for insulin during these periods. When recovering and maintaining their own secretion of insulin, the patient is again transferred to his usual sugar-lowering therapy.
Daily sugar-lowering therapy in the vast majority of cases during this period is canceled. Short-acting insulin is prescribed under the control of glycemia and prolonged insulin at bedtime. The number of insulin injections depends on the level of glycemia and the patient’s condition.
Temporary long-term insulin therapy is prescribed in the following situations:
To eliminate the state of glucose toxicity until b-cell function is restored.
The presence of temporary contraindications to the use of PSSP (hepatitis, pregnancy, etc.).
Long-term inflammatory processes (diabetic foot syndrome, exacerbation of chronic diseases).

In the presence of contraindications to the intake of PSSP, everyday hypoglycemic therapy is canceled, in the absence of such, it can be saved. If there are contraindications to taking PSSP, prolonged insulin is prescribed before breakfast and at bedtime. In case of postprandial hyperglycemia with this treatment, short-acting insulin is prescribed before meals. In the absence of contraindications to taking PSSP, the resulting hypoglycemic drugs are not canceled, and prolonged insulin is prescribed before bedtime and, if necessary, before breakfast. To eliminate glucose toxicity or recover, the patient is transferred to the usual hypoglycemic therapy.

Permanent insulin therapy is prescribed in the following cases:
when b-cells are depleted and both basal and stimulated secretion of intrinsic insulin are reduced (C-peptide basal <0.2 nmol / L, stimulated C-peptide <0.6 nmol / L);
in the presence of contraindications to the use of PSSP (diseases of the liver, kidneys, blood, individual intolerance to PSSP);
in the presence of contraindications or inefficiency of metformin to normalize fasting glycemia.

Daily hypoglycemic therapy is canceled. Prescribe a combination of short-acting insulin before main meals and prolonged insulin before bedtime and before breakfast. In the presence of contraindications or inefficiency of metformin to normalize fasting glycemia, combination therapy is prescribed in the form of PSM during the day and prolonged insulin before bedtime.
Indications for mono-insulin therapy for type 2 diabetes are:
insulin deficiency, clinically and laboratory confirmed;
absolute contraindications to the use of PSSP (diseases of the kidneys, liver, blood, pregnancy, lactation).

Monoinsulin therapy for type 2 diabetes can be prescribed both in the form of traditional and in the form of intensified insulin therapy.
Intensified IT can only be prescribed to patients with preserved intelligence, well-trained principles of diabetes therapy, tactics of behavior in emergency conditions, self-control and, without fail, having the means to implement it. Considering that intensified IT can increase the risk of hypoglycemic conditions, which are especially dangerous in the presence of cardiovascular diseases, this type of insulin therapy is not recommended for people with acute myocardial infarction, acute cerebrovascular accident, or people with unstable angina. Typically, such patients are prescribed prolonged insulin twice a day, and the dose of short insulin is set individually, depending on the amount of carbohydrate planned for intake with food and the level of preprandial glycemia.
Modern criteria for the compensation of type 2 diabetes, proposed by the European NIDDM Policy Group (1993), suggest fasting glycemia below 6.1 mmol / l, and 2 hours after a meal – below 8.1 mmol / l, glycated HbA1C hemoglobin below 6.5 %, aglucosuria, aketonuria, normolipidemia, blood pressure below 140/90 mm RT. Art., body mass index below 25.
Achieving compensation of type 2 diabetes is carried out in several stages. At the first stage of treatment, decompensation of the disease is eliminated (fasting glycemia below 7.8, and after eating below 10.0 mmol / l). It is proved that, on the one hand, the indicated glycemia already reduces the manifestation of glucose toxicity and helps to normalize insulin secretion, and on the other hand, with this level of fasting glycemia, the risk of developing hypoglycemic episodes is almost completely eliminated, especially at the most dangerous night time.
The next important stage in the treatment of patients was the solution of the question of individual criteria for compensating for the disease in each individual patient.
It is known that one of the criteria for compensating type 2 diabetes is fasting glycemia below 6.1 mmol / L. At the same time, it is widely believed that in elderly people the compensation criteria may be less stringent, given the risk of hypoglycemia that they do not recognize well. However, there is no doubt that the decompensation of diabetes in senile individuals activates catabolic processes, predisposes to the development of acute and accelerates the progression of late complications of diabetes. A ten-year observation of elderly patients suffering from type 2 diabetes showed that with decompensation of the disease, the frequency of strokes and cardiovascular diseases increases sharply, regardless of the duration of the disease (M.Uusitupa et al., 1993). Moreover, mortality from the described causes progressively increases with an increase in HbA1C from 8.7% to 9.1% (J. Kuusisto, L. Mykkanen, K. Pyorala et al., 1994).
An analysis of the literature data and our own experience in achieving compensation of the disease in patients with type 2 diabetes allows us to state the following: from our point of view, regardless of the patient’s age, the patient’s intellect and personal resources are the priority positions in choosing compensation criteria in each case self-control, daily glycemic control and a high level of knowledge that allows the patient to make the right decision on the basis of the data received by him during self-control. In the event that the patient meets the above criteria and, in addition, he does not have a history of unstable angina, suffered from an acute violation of cerebral circulation or myocardial infarction, it should gradually proceed to the next goal of therapy – to achieve fasting glycemia below 6.1 mmol / l