Diabetes mellitus - Overview of information

A violation of glucose regulation (impaired glucose tolerance or impaired fasting glucose) is an intermediate, possibly transient, condition between normal glucose metabolism and diabetes, which often develops with age, is a significant risk factor for the development of diabetes mellitus and can be observed many years before the onset of sugar diabetes. It is also associated with an increased risk of developing cardiovascular disease, but typical diabetic microvascular complications usually do not develop.

To date, not only genetic, but also pathophysiological heterogeneity of diabetes mellitus has been fully proved. According to the classification of the disease, proposed by the WHO Expert Committee (1981), two main pathogenetic forms of the disease are distinguished: type I diabetes (insulin-dependent) and type II diabetes (non-insulin-dependent). Pathophysiological, clinical and genetic differences of these types of diabetes are presented in Table. 8.

Characteristics of I and II types of diabetes mellitus

In addition to other signs, significant differences are also observed in the degree of concordance (reciprocal incidence) of identical twins. Of course, a 50% degree of concordance in monozygotic twins in groups of patients with type 1 diabetes is significantly higher than among dizygotic twins or siblings, which indicates that the genetic factor plays a significant role in the pathogenesis of the disease. The discordance in this group of twins, which is 50%, indicates the greater role of other factors (besides genetic ones), for example, viral diseases. It is suggested that the HLA system is a genetic determinant determining the sensitivity of the pancreatic beta cells to viral antigens, or reflects the degree of antiviral immunity.

Thus, type 1 diabetes is due to the presence of mutant diabetic genes in chromosome 6, related to the HLA system, which determines the individual, genetically conditioned response of the organism to various antigens. Mutant genes, apparently, are associated with the HLAD-segment. In addition to diabetic HLA haplotypes, protective leukocyte antigens, for example, HLA B7 and A3, DR2, that can interfere with the development of diabetes, despite the presence of mutant genes, have also been detected. The risk of developing diabetes is significantly greater in patients with two HLA-B8 and B15 than with one of them.

Despite the fact that type I diabetes is characterized by association with HLA antigens and certain clinical and pathophysiological parameters, it is heterogeneous. Depending on the pathogenetic features, Type I diabetes is divided into two subtypes: 1a and Ib. Subtype 1a is associated with a defect of antiviral immunity, so the pathogenetic factor is a viral infection that causes the destruction of beta cells of pancreatic islets. It is believed that smallpox viruses, Coxsackie B, adenovirus have tropism to the islet tissue of the pancreas. Destruction of islets after a viral infection is confirmed by peculiar changes in the pancreas in the form of "insulites", expressed in infiltration by lymphocytes and plasma cells. When there is a "viral" diabetes in the blood, circulating autoantibodies to islet tissue are found. As a rule, after 1-3 years the antibodies disappear.

Diabetes 1b is 1-2% in relation to all patients with diabetes. This subtype of diabetes is considered as a manifestation of autoimmune disease, which is confirmed by the frequent combination of type 1b diabetes with other autoimmune endocrine and non-endocrine diseases: primary chronic hypocorticism, hypogonadism, autoimmune thyroiditis, toxic goiter, hypoparathyroidism, vitiligo, pernicious anemia, nesting baldness, rheumatoid arthritis. In addition, the circulating autoantibodies in islet tissue are detected before the detection of clinical diabetes and are present in the blood of patients for almost the entire period of the disease. The pathogenesis of 1b subtype of diabetes is associated with a partial genetically determined defect in the immunological surveillance system, i.e., with inferiority of suppressor T-lymphocytes, which normally inhibit the development of forbid clones of T-lymphocytes directed against tissue proteins of the organism.

Differences between the 1a- and 1 _b subtype of diabetes confirmed the predominance of HLA B15, DR4 subtype when 1a-and HLA B8, DR3 - at 1b-subtype. Thus, subtype 1a of diabetes is caused by a violation of the body's immune response to certain exogenous antigens (viral), and subtype Ib is an organ-specific autoimmune disease.

Type II diabetes (insulin-dependent) is characterized by a large concentration of family forms of the disease, a significant influence on its manifestation of environmental factors, the main one being obesity. Since this type of diabetes is combined with hyperinsulinemia, lipogenesis processes leading to obesity predominate in patients. Thus, on the one hand, it is a risk factor, and on the other - one of the early manifestations of diabetes. The insulin-independent type of diabetes is also pathogenetically heterogeneous. For example, the clinical syndrome of chronic hyperglycemia, hyperinsulinemia and obesity can be observed with excessive secretion of cortisol ( Isenko-Cushing's disease ), growth hormone (acromegalia), glucagon (gluconoma), excess production of antibodies to endogenous insulin, in certain types of hyperlipidemia, etc. Clinical manifestations of type II diabetes are expressed in chronic hyperglycemia, which can be treated with a diet that helps to reduce body weight. Usually, ketoacidosis and diabetic coma are not observed in patients. Since type II diabetes occurs in people older than 40 years, the general condition of patients and their ability to work often depend on concomitant diseases: hypertension and complications of atherosclerosis, which occur in diabetic patients several times more often than in the general population of the corresponding age group. The proportion of patients with type II diabetes is approximately 80-90%).

One of the most serious manifestations of diabetes, regardless of its type, is diabetic microangiopathy and neuropathy. In their pathogenesis, a significant role is played by metabolic disorders, mainly hyperglycemia, characteristic of diabetes mellitus. Defining processes that develop in patients and underlying the pathogenesis of microangiopathy are glycosylation of body proteins, disruption of cellular function in insulin-independent tissues, changes in the rheological properties of blood and hemodynamics. In the 70s of our century it was found that in patients with decompensated diabetes the content of glucosylated hemoglobin increases in comparison with healthy ones. Glucose by a nonenzymatic process reacts with the N-terminal amino group of the B chain of the hemoglobin A molecule to form a ketoamine. This complex is found in erythrocytes for 2-3 months (the lifetime of the erythrocyte) in the form of small fractions of hemoglobin A _1c or A _1abc. At present, the possibility of glucose addition to the formation of ketoamine and to the A chain of the hemoglobin molecule has been proved. A similar process of increased glucose incorporation in blood serum proteins (with the formation of fructosamine), cell membranes, low-density lipoproteins, peripheral nerve fibers, collagen, elastin and lens was found in most patients with diabetes mellitus and experimental diabetic animals. Changes in the basement membrane proteins, their high content in endothelial cells, aortic collagen and the basement membrane of the renal glomerulus not only can disrupt the cell function, but also promote the formation of antibodies to altered vascular wall proteins (immune complexes) that can participate in the pathogenesis of diabetic microangiopathy.

In the pathogenesis of the disturbance of the cellular function of insulin-independent tissues, the enhanced stimulation (against the background of hyperglycemia) of the enzymatic polyol pathway of glucose metabolism plays a role. Glucose in proportion to its concentration in the blood enters the cells of insulin-independent tissues, where it, without undergoing phosphorylation, turns under the influence of the enzyme aldose reductase in the cyclic alcohol - sorbitol. The latter, with the help of another enzyme, sorbitol dehydrogenase, is converted to fructose, which is utilized without the participation of insulin. The formation of intracellular sorbitol occurs in the cells of the nervous system, pericyte of the retina, pancreas, kidneys, lens, vessels walls containing aldose reductase. The accumulation of excess amount of sorbitol in cells increases osmotic pressure, causing cellular edema, and creates conditions for disrupting the function of the cells of various organs and tissues, contributing to the disturbance of microcirculation.

Hyperglycemia can disrupt metabolism in the nervous tissue in various ways: by lowering the sodium-dependent absorption of myoinositol and (or) increasing the polyol pathway of glucose oxidation (the myo-inositol content in the nervous tissue decreases), or by disturbing the metabolism of phosphoinositide and sodium potassium-ATPase activity. In connection with the expansion of glycosylation of tubulin, the microtubule function of axons and transport of myoinositis, its intracellular binding, may be disrupted. These phenomena contribute to a decrease in nerve conduction, axonal transport, water cellular balance and cause structural changes in nerve tissues. The clinical variability of diabetic neuropathy, independent of the severity and duration of diabetes, allows one to think about the possibility of influencing such pathogenetic factors as genetic and external (nerve compression, alcohol, etc.).

In the pathogenesis of diabetic microangiopathy, in addition to the previously mentioned factors, hemostasis can also play a role. In patients with diabetes mellitus, there is an increase in platelet aggregation with an increase in thromboxane A ₂ production , an increase in the metabolism of arachidonic acid in platelets and a decrease in their half-life, disruption of prostacyclin synthesis in endothelial cells, a decrease in fibrinolytic activity and an increase in von Willebrand factor, which may contribute to the formation of microthrombi in the vessels. In addition, the increase in blood viscosity, slowing of blood flow in the retinal capillaries, as well as tissue hypoxia and a decrease in oxygen release from hemoglobin A1, may be involved in the pathogenesis of the disease, as evidenced by a decrease in 2,3-diphosphoglycerate in erythrocytes.

In addition to the aforementioned andogenetic factors in the pathogenesis of diabetic microangiopathy and nephropathy, hemodynamic changes in the form of microcirculatory disturbances can play a role. It is noted that in the initial stage of diabetes, capillary blood flow increases in many organs and tissues (kidney, retina, skin, muscle and fat tissue). This, for example, is accompanied by an increase in glomerular filtration in the kidneys with the growth of the transglomerular pressure gradient. It was suggested that this process can cause the protein to enter through the capillary membrane, accumulate it in the mesangium, followed by the proliferation of mesangium and lead to intercapillary glomerulosclerosis. Clinically, patients develop transitory and then permanent proteinuria. Confirmation of this hypothesis is considered by the authors to be the development of glomerulosclerosis in experimental diabetic animals after partial nephrectomy. TN Hostetter et al. Proposed the following scheme of the sequence of development of kidney damage: hyperglycemia - increased renal blood flow - increased transglomerular hydrostatic pressure (with subsequent deposition of protein in the vessel wall and basal membrane) - protein filtration (albuminuria) - mesangium thickening - glomerulosclerosis - compensatory filtration increase in the remaining glomeruli - renal failure.

Diabetic microangiopathy and histocompatibility antigens (HLA). In 20-40% of patients with a 40-year duration of type I diabetes there is no diabetic retinopathy, which suggests a significant role in the development of microangiopathy, not only metabolic disorders, but also a genetic factor. Controversial data were obtained from the study of the association of HLA antigens and the presence or absence of diabetic proliferative retinopathy or nephropathy. In most studies, there has been no association of neuropathy with the nature of the detected HLA antigens. Given the heterogeneity of type I diabetes, the HLA phenotype DR3-B8 is characterized by the predominance of constantly circulating antibodies to pancreatic islets, increased formation of circulating immune complexes, weak immune response to heterologous insulin, and poorly expressed manifestations of retinopathy. Another form of type I diabetes with the B15-Cw3-DR4 HLA phenotype is not combined with autoimmune diseases or persistent circulating antibodies to islet cells and occurs at an earlier age, often accompanied by proliferative retinopathy. An analysis of published studies that examined the possible association of HLA antigens with diabetic retinopathy in more than 1,000 patients with type I diabetes showed that an increased risk of developing proliferative retinopathy was observed in patients with the HLA B15-DR4 phenotype, while HLA B18- the phenotype plays a protective role in the risk of severe retinopathy. This is explained by the longer secretion of endogenous insulin (C-peptide) in patients with HLA B18 and B7 phenotypes, as well as frequent association with the Bf allele of theperdin, which is localized in the short arm of chromosome 6 and may be related to retinopathy.

Pathanatomy

Changes in the islet apparatus of the pancreas undergo a kind of evolution, depending on the duration of diabetes mellitus. As the duration of the disease increases in patients with type I diabetes, there is a decrease in the number and degeneration of B cells with an unchanged or even increasing content of A and D cells. This process is the result of infiltration of the islets with lymphocytes, ie, a process called insulitis that is related to the primary or secondary (against the background of viral infections) autoimmune pancreatic lesion. Insulin-deficient type of diabetes is also characterized by diffuse fibrosis of the islet system (in about 25% of cases), especially when diabetes is combined with other autoimmune diseases. In most cases, type I diabetes mellitus develops the hyalinosis of the islets and the accumulation of hyaline masses between the cells and around the blood vessels. In the early stages of the disease there are foci of B-cell regeneration completely disappearing with increasing duration of the disease. In a significant number of cases, the residual secretion of insulin, caused by partial preservation of B cells, was noted. Type II diabetes is characterized by a certain decrease in the number of B cells. In the microcirculation vessels, a thickening of the basal membrane is detected due to the accumulation of the SHIC-positive material represented by glycoproteins.

Retinal vessels undergo various changes depending on the stage of retinopathy: from the appearance of microaneurysms, microthrombosis, hemorrhages and occurrence of yellow exudates to the formation of new vessels (neovascularization), fibrosis and retinal detachment after vitreous hemorrhage with the subsequent formation of fibrous tissue.

With diabetic peripheral neuropathy segmental demyelination is observed, degeneration of axons and connective nerves. In sympathetic ganglia, large vacuoles, giant neurons with degeneration phenomena, swelling of dendrites are found. In sympathetic and parasympathetic neurons - thickening, fragmentation, hyperagentophilia.

The most typical for diabetes is diabetic nephropathy - nodular glomerulosclerosis and tubular nephrosis. Other diseases, such as diffuse and exudative glomerulosclerosis, arteriosclerosis, pyelonephritis and necrotic papillitis, are not specific for diabetes mellitus, but are associated with it much more often than with other diseases.

Nodular glomerulosclerosis (intercapillary glomerulosclerosis, Kimmelstyle-Wilson syndrome) is characterized by the accumulation of PAS-positive material in the mesangium in the form of nodules along the periphery of the branches of the glomerular capillary loops and thickening of the basement membrane of the capillaries. This type of glomerulosclerosis is specific for diabetes mellitus and correlates with its duration. Diffuse glomerulosclerosis is characterized by a thickening of the basement membrane of the capillaries of all glomerular sections, a decrease in the lumen of the capillaries and their occlusion. It is believed that diffuse glomerulosclerosis can precede nodular glomerulosclerosis. The study of kidney biopsy specimens in patients with diabetes mellitus, as a rule, makes it possible to detect a combination of changes characteristic of both nodular and diffuse lesions.

Exudative glomerulosclerosis is expressed in the accumulation of a homogeneous eosinophilic material resembling fibrinoid between the endothelium and the basal membrane of the Bowman capsule in the form of lipogialin cups. This material contains triglycerides, cholesterol and PAS-positive polysaccharides.

Typical for tubular nephrosis is the accumulation of vacuoles containing glycogen in epithelial cells of predominantly proximal tubules and deposition in their cytoplasmic membranes of a PAC-positive material. The degree of expression of these changes correlates with hyperglycemia and does not correspond to the nature of the disturbances in tubular function.

Nephrosclerosis is the result of atherosclerotic and arteriolosclerotic lesions of small arteries and arterioles of the kidneys and is found, according to sectional data, in 55-80% of cases against diabetes mellitus. Hyalinosis is observed in the efferent and afferent arterioles of the juxtaglomerular apparatus. The nature of the pathological process does not differ from the corresponding changes in other organs.

Necrotic papillitis is a relatively rare acute form of pyelonephritis, characterized by ischemic necrosis of the renal papillae and vein thrombosis on the background of a violently flowing infection. Patients develop fever, hematuria, renal colic and transient azotemia. In the urine, scraps of the renal papillae are often found due to their destruction. Necrotic papillitis is much more common in patients with diabetes mellitus.