ETIOLOGY OF DIABETES
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.
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