ETIOLOGY OF DIABETES

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Diabetes develops due to a deficiency of insulin (IDDM), or failure of its effects (NIDDM).

Causes

I. Insulin deficiency can occur under the influence of biological factors, chemical, physical nature, as well as in inflammatory processes of the pancreas

1. Biological factors

a) Genetic defects in β-cells of the islets of Langerhans. There is a pronounced dependence of frequency hypoinsulism in patients with IDDM of expression of certain Ag HLA. These include Ar glycoproteins encoded by alleles HLA-DR3, HLA-DR4, HLA-DQ, B1. Genetic defects cause inclusion autoaggressive immune mechanisms of pancreatic injury (due to occurrence of the immune system to foreign Ar) and low insulin synthesis (for example, when repression of genes encoding enzymes synthesizing insulin).

b) Immune factors: Ig, cytotoxic T lymphocytes and cytokines produced by them damaging β-cells and the immune reaction autoaggression implement. In patients with insulin deficiency detect several types of specific AT:

- To the cytoplasmic Ag - ICA (from the English islet cell autoantibody - autoantibodies to islet cell proteins.);

- A protein with a molecular mass of 64 kDa, detectable in the cytoplasmic membrane of β-cells. AT These often show before the other signs of diabetes. In this regard, they are referred to the number of initiators of the immune response of anti-β-autoaggression cell;

- Molecules of insulin.

c) Viruses, tropic to the β-cells:. Coxsackie B4, hepatitis B, measles, chicken pox, mumps, rubella, etc. For example, in intrauterine rubella diabetes develops in about 20% of newborns. Viruses are responsible for:

- Direct cytolytic activity against β-cells,

- Initiation of immune processes against β-cells,

- The development of inflammation in the areas of location of β-cells of the islets of Langerhans - insulitis.

g) endogenous toxic substances that damage the β-cells, the most "aggressive" of them - allokean. It is formed in excess as a result of a pyrimidine metabolism and insulin blocks the formation. The latter is associated with a low content of SH-groups (required for inactivation of alloxan) in β-cells.

2. Chemical factors alloxan, high doses of ethanol, cytostatics and other drugs (e.g., anticancer agent streptozocin).

3. Physical factors: ionizing radiation, initiating activation lipoperoxide processes, mechanical trauma of the pancreas, tumor compression. These and other factors lead to the physical nature of the death of islet β-cells.

a) Inflammation

Inflammatory processes occurring in the pancreas by the action of biological factors (mainly of microorganisms), chemical and physical nature. Chronic pancreatitis is about 30% of cases the cause of insulin deficiency.

II. Effects of insulin deficiency develops under the influence of the causes of neuro or psychogenic nature contrinsular factors, as well as due to defects in insulin receptors and postreceptor violations in target cells.

1. Neuro - and / or psychogenic factors:

- Activation of the neurons of the posterior hypothalamus nuclei, leading to an increase in tone of the sympathetic-adrenal and hypothalamic-pituitary-adrenal system. This results in a significant and sustained increase in blood contrinsular hyperglycemic hormones: epinephrine, norepinephrine (adrenal origin), glucocorticoids, and therefore, the relative lack of insulin effects.

- Re-development of protracted stress reactions. These include activation of the sympathetic-adrenal and hypothalamic-pituitary-adrenal system. This leads to an increase in blood levels of catecholamines, glucocorticoids, thyroid hormones. All of them are functional antagonists of insulin.

2. Contrinsular factors:

- Excessive activation insulinase hepatocytes. This protease hydrolyzes insulin molecule.

- AT to endogenous insulin.

- Increase in blood levels of contrinsular (hyperglycemic) hormones: catecholamines, glucagon, glucocorticoids, growth hormone, T3 and T4. Hyperproduction these hormones can be observed in the corresponding tumors of the endocrine glands or prolonged stress.

- Increased concentration in blood plasma proteins, insulin binding molecule.

2. Factors causing blockage, destruction or decrease the sensitivity of insulin receptors:

- Ig, imitating the structure of the insulin molecule. Such Ig receptors interact with insulin, block them, thus preventing access of insulin to the receptor molecules.

- Ig, destroying the insulin receptor and / or zone perireceptors target cells.

- Prolonged excess insulin causes hypoconcaveation target cells to the hormone.

- Hydrolases released from lysosomes and activates the inside and outside of the damaged or decaying cells (for example, a total of hypoxia, disorders of external respiration and circulation).

- Free radicals and products Spolli (for example, when re-prolonged stress, atherosclerosis, cardiovascular disease).

3. Factors that violate implementation of the effects of insulin in target cells:

- The damaging of the membrane and / or cell receptors to the insulin.

- A denaturing and / or disrupting cellular enzymes.

The most common causes of damage to cell membranes and enzymes are over-activity of lysosomal enzymes, excessive formation of reactive oxygen species, free radicals and lipid hydroperoxide.

These and other pathogenic agents inhibit the transport of glucose into the cells, the formation of cAMP, the transmembrane transport of Ca2 + ions and of Mg2 +, necessary for the implementation of intracellular effects of insulin.

Risk factors

A large number of risk factors for diabetes.

1. Overweight. Obesity is detected in more than 80% of patients with NIDDM. This increases hepatic insulin resistance, adipose and other tissues - targets insulin.

2. Persistent and significant hyperlipidemia.

Both factors stimulate the production of contrinsular hormones and hyperglycemia. This in turn activates insulin synthesis of β-cells, leading to their "depletion" and damage.

3. Hypertension, leading to disruption of the microcirculation in the pancreas.

4. Hereditary or congenital predisposition. It is believed that patients with diabetes immunoagressive predisposition to the disease determine HLA genes.

Patients with NIDDM a predisposition to diabetes has polygenic character. In the presence of diabetes in a parent ratio of their sick children to healthy can be 1: 1.

5. Female gender.

6. Repeated stress reaction. They are accompanied by a persistent increase in blood levels of contrinsular hormones.

7. The combination of several risk factors increases the risk of diabetes in the 20-30 times.