PATHOGENESIS OF DIABETES

The following are the links of the pathogenesis of diabetes with insulin deficiency (resulting in developing IDDM) and with insufficient effects of insulin (and therefore developing NIDDM).

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Insulin deficiency

The main pathogenesis.

Exposure to pathogenic factors causing damage to the pancreatic β-cells. This action leads to the suppression of the processes:

- Biosynthesis proinsulin

- Splitting of proinsulin to insulin

- Transport of proinsulin to the Golgi apparatus

- Devesiculationi and release insulin into the bloodstream

- Vesiculation insulin

When insulin deficiency occurs:

- Damage and loss of β-cells of the islets of Langerhans,

 - Reduction of the total β-cell mass,

- Inhibition of the synthesis and release of insulin into the blood from damaged β-cells.

In most cases (possibly even all) of the pathogenesis of insulin deficiency is common link: immunoagressive development process. This process typically takes several years and is accompanied by the gradual destruction of β-cells.

Diabetes Symptoms usually appear at break of about 75-80% β-cells (which can be detected earlier on a different background, "precipitating" states - diseases, intoxications, stress, glucose metabolism disorders, binge eating and other endocrinopathy). The remaining 20-25% of cells usually destroyed during the subsequent 2-3 years.

In the dead of diabetes patients pancreas weight is an average of 40 g (80-85 g norm). The mass of β-cells (healthy individuals about 850 mg) is negligible or not is determined.

Key links immunoagressive version of the pathogenesis of diabetes mellitus.

1. The introduction of the organism is genetically predisposed to diabetes people of foreign Ar carrier. The most common are viruses, at least - other microorganisms.

2. Absorption of foreign antigen presenting cells Ag, Ag processing and presentation of it in conjunction with the Ag HLA (presentation) helper T lymphocytes.

3. The formation of immune AT and activated lymphocytes against specific foreign Ag.

4. Action AT and activated lymphocytes:

- Foreign Ag: its destruction and elimination from the body, with the participation of phagocytes;

- Antigenic structures β-cells having a similar structure to the alien Ag (assume that such an endogenous Ag, like an alien, may be a protein with Mr 64 kDa);

- Cells containing such Ar, are attacked by the body's system of immunobiological surveillance, perceiving their own Az for alien. This phenomenon is referred to as "cross-immune response." During this reaction, β-cells are destroyed and the individual proteins are denatured and autoantigens.

5. Absorption, processing and presentation of both the lymphocytes alien Ar and newly formed β-cell autoantigens monocytes / macrophages.

The process of the immune autoaggression potentiated the synthesis and transport to the surface of damaged β-cells Ag HLA class I and II. Said Ar stimulate helper T cells and consequently - specific Ig production and differentiation of cytotoxic T-lymphocytes. Immune autoaggression against their β-cells increases. Increasing scale islet damage the appliance.

6. Migration in regions of damaged and destroyed by the pancreatic β-cells phagocytes.

7. cytolytic effect on leukocyte β-cells by lysosomal enzymes, generation of large amounts of reactive oxygen species, free radicals of organic substances, the activation process lipoperoxide cytokines (γ-IFN, TNF-β, IL-1).

8. The destruction of β-cells is accompanied by the release of these "foreign" to the immune system proteins (normally they are only intracellularly and in the blood does not fall): heat shock, cytoplasmic ganglioside, proinsulin.

9. Absorption macrophages said cytoplasmic proteins β-cells, its processing and presentation to lymphocytes. This causes the next episode of the destruction of the immune attack of additional β-cells. By reducing their weight to 75-80% of normal "suddenly" appear clinical signs of diabetes.

Signs in relation to the activation of β-cells of the immune surveillance system may disappear with time. With the death of β-cells decreases and the stimulus to the immune response autoaggression. So, AT level in Ag β-cells is significantly reduced by 1-1.5 years after their first detection.

Pathogenesis of absolute insulin deficiency caused by the action of chemical pancreatic factors.

Chemical pancreatropic agents cause direct damage to the β-cells, damage to the membranes and enzymes, and as a result to the denaturation of proteins and the appearance of autoantibodies. The same process can cause a chain and other mechanisms - the action of the primary chemical pancreatropic agent stimulates the formation of an excess of reactive oxygen species and activation of lipid peroxidation. The result is a destruction of β-cells and insulin deficiency.

The mechanism of absolute insulin deficiency caused by the influence of physical pathogenic factors.

Pathogenic agents physical nature

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Damage and destruction of β-cells

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The emergence of autoantigens

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Education and cytotoxic effect on β-cells and lymphocytes AT autoaggressive

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The destruction of β-cells

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insulin deficiency

Lack of insulin effects

The implementation of various embodiments of the pathogenesis of diabetes with insulin deficiency effects occur with normal or even elevated its synthesis and incretion in the blood (the developing NIDDM).

Contrinsular factors

1. insulinase.

Mechanisms of activation insulinase:

- An increase in the blood of glucocorticoids and / or growth hormone (which is often observed in patients with diabetes);

- Deficiency of zinc and copper ions, reducing the normal activity insulinase;

Since insulinase begins to rapidly synthesized by hepatocytes in puberty, this mechanism is an important pathogenesis of juvenile diabetes.

2. The proteolytic enzymes. They can come from extensive foci of inflammation and destroy the insulin (for example, cellulitis, peritonitis, infection of burn surface).

3. AT to blood insulin.

4. Substances insulin molecule binding and thereby block the interaction with the insulin receptor. These include:

- Plasma insulin inhibitors of protein nature (eg, the individual fractions α- and β-globulin).

Insulin bound to plasma proteins does not show activity in all tissues except the fat. The final conditions for the cleavage of the protein molecule, and contact with specific insulin receptors.

- Β-lipoproteins. The synthesis of β-LP in increased amounts indicated in patients with overproduction of growth hormone. β-form LP large - molecular complex with insulin, insulin in the composition is not able to interact with its receptor.

The elimination or reduction of the effects of insulin on target tissues

The elimination or reduction of the effects of insulin on target tissues is achieved owing to the effect of excess hormones hyperglycemic insulin metabolic antagonists. These include catecholamines, glucagon, glucocorticoids, growth hormone, and iodine-containing thyroid hormones.

Long-term and significant hyperglycemia stimulates increased production of β-cell insulin. However, this may not be sufficient to normalize HPA, as long hyperactivation pancreatic islets leading to damage of β-cells.

Insulin resistance

Violation implement the effects of insulin at target cells known as insulin resistance. Known receptor and postreceptor mechanisms of this phenomenon.

The receptor mechanisms

1. "Screening" (closing) insulin receptor Ig. Recent specifically react with the receptor proteins themselves and / or perireceptors zone. Ig molecule thus make it impossible interaction of insulin and its receptor. Under these conditions, the receptor itself and the cell membranes are not damaged.

2. Hypoconcaveation target cells to insulin. It is caused by prolonged increase in insulin concentration in blood and the interstitium.

- Hypoconcaveation cells is the result of increasing the number of low-affinity on the surface of cells to insulin receptor and / or decrease the total number of insulin receptors.

- Hypoconcaveation observed in individuals suffering from overeating, which causes overproduction of insulin.

3. The destruction and / or modification of the conformation of the insulin receptor are determined by:

- Antireceptors the AT, is synthesized by changing the structure of the receptor (eg, as a result of acceding to it in the form of the hapten drug or toxin);

- An excess of free radicals and products at process lipoperoxide hypoxia deficiency antioxidants - tocopherol, ascorbic acid, etc;

- Defects in genes encoding the synthesis of the insulin receptor polypeptides.

postreceptor mechanisms

- Violations of protein phosphorylation of target cells, which disrupts intracellular processes "recycling" of glucose.

- Defects in the target cells transmembrane glucose transporters. They are mobilized in time insulin interaction with its receptor on the cell membrane. Transmembrane glucose transporters failure is detected in patients with diabetes in conjunction with obesity.