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DIABETES MELLITUS
Diabetes mellitus is heterogenic diseases group which arise on base of absolute
or relative insulin insufficiency and have hyperglicemia as general symptom.
Classification of diabetes mellitus up to nows remains clinical. Main types
insulin-dependent diabetes mellitus and insulin-independent diabetes mellitus.
These two diabetes types affect the majority of patient.
There are counts six millions of patient with insulin-dependent diabetes mellitus
in the world. This is mainly illness of white race. It occur more frequent in highly
developed countries (Finland, Italy, Sweden, Denmark, Canada, Norway, USA,
England). There are about 100 millions of patient with insulin-dependent
diabetes mellitus. They consist 85 % of all diabetics. They belong to mainly
native population of USA (american indians), Fiji, South Africa, India, Polynesia.
Causes of Diabetes Mellitus
Diabetes mellitus is caused by an absolute or relative lack of insulin that, among
other consequences, leads to an increase in plasma glucose concentration The
disease was given its name because of the glucose excretion in the urine. The
disease can be classified into several types, depending on its cause and course.
This classification is useful, even though it is greatly simplified.
In type I (insulin-dependent diabetes mellitus [IDDM], previously called juvenile
diabetes) there is an absolute lack of insulin, so that the patient needs an
external upply of insulin. The condition is caused by a lesion in the beta cells of
the pancreas, as a rule produced by an autoimmune mechanism that may, in
certain circumstances, have been triggered by a viral infection. The pancreatic
islets are infiltrated by T lymphocytes and autoantibodies against islet tissue
(islet cellantibodies [ICA]) and insulin (insulin autoantibodies [IAA]) can be
detected. ICA may in some cases be detected years before the onset of the
disease. After the death of the beta cells, the ICA again disappear. 80% of
patients form antibodies against glutamatedcarboxylase expressed n the beta
cells. Type I diabetes mellitus occurs more frequently in the carriers of certain
HLA antigens (HLA-DR3 and HLA-DR4), i.e., there is a genetic disposition.
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Type II (non-insulin-dependent diabetes mellitus [NIDDM], formerly called
maturityonset diabetes) is by far the most common form of diabetes. Here, too,
genetic disposition is important. However, there is a relative insulin deficiency:
the patients are not necessarily dependent on an exogenous supply of insulin.
Insulin release can be normal or even increased, but the target organs have a
diminished sensitivity to insulin.
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Most of the patients with type II diabetes are overweight. The obesity is the
result of a genetic disposition, too large an intake of food, and too little physical
activity. The imbalance between energy supply and expenditure increases the
concentration of fatty acids in the blood. This in turn reduces glucose utilization
in muscle and fatty tissues. The result is a resistance to insulin, forcing an
increase of in sulin release. The resulting down-regulation of the receptors
further raises insulin resistance. Obesity is an important trigger, but not the sole
cause of type II diabetes. More important is the already existing genetic
disposition to reduced insulin sensitivity. Frequently, insulin release has always
been abnormal. Several genes have already been defined that promote the
development to obesity and type II diabetes. Among other factors, the genetic
defect of a mitochondrial decoupling protein limits substrate consumption. If
there is a strong genetic disposition, type II diabetes can already occur at a
young age (maturity-onset diabetes of the young [MODY]).
Reduced insulin sensitivity predominantly affects the insulin effect on glucose
metabolism, while the effects on fat and protein metabolism are still well
maintained.
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Glucose rugulation
Thus, type II diabetics tend especially toward massive hyperglycemia without
corresponding impairment of fat metabolism (ketoacidosis). Relative insulin
deficiency can also be caused by autoantibodies against receptors or insulin as
Pathogenesis of DM
that glucose is excreted in the urine. This results in anosmotic diuresis withrenal
loss of water (polyuria), Na+, and K+, dehydration, and thirst. Despite the renal
loss of K+, there is no hypokalemia because the cells give up K+ as a result of
reduced activity of Na+-K+ -2 Clcotransport and of Na+-K+-ATPase. The
extracellular K+ concentration, which is therefore more likely to be high,
disguises the negative K+balance. Administration of insulin then causes a lifethreatening hypokalemia. Dehydration leads to hypovolemia with corresponding
impairment of the circulation. The resulting release of aldosterone increases the
K+ deficiency, while the release of epinephrine and glucocorticoids exacerbates
the catabolism. The reduced renal blood flow diminishes the renal excretion of
glucose and thus encourages the hyperglycemia.
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The cells further lose phosphate (P) and magnesium that are also excreted by
the kidney. If there is an insulin deficiency, proteins are broken down to amino
acids in muscles and other tissues. This breakdown of muscles will, together with
electrolyte abnormalities, lead to muscular weakness. Prevailing lipolysis leads to
release of fatty acids into blood (hyperlipidacidemia). The liver produces
acetoacetic acid and -hydroxybutyric acid from the fatty acids. Accumulation of
these acids leads to acidosis, which forces the patient to breathe deeply
(Kussmaul breathing). Some of the acids are broken down to acetone (ketone
bodies). In addition, triglycerides are formed in the liver from fatty acids and
incorporated into VLDL. As the insulin deficiency delays the breakdown of
lipoproteins, the hyperlipidemia is further aggravated. Some of the triglycerides
remainin the liver anda fatty liver will develop. The breakdown of proteins and fat
as well as polyuria will result in weight loss. The abnormal metabolism,
electrolyte disorders and the changes in cell volume brought about by changed
osmolarities can impair neuronal function and cause hyperosmolar or
ketoacidotic coma. The main effects of relative insulin deficiency are
hyperglycemia and hyperosmolarity, while in absolute insulin deficiency the
consequences of increased proteolysis and lipolysis (ketoacidosis) are added to
these effects.
To avoid swelling, the cells compensate by giving off myoinositol which then,
however, will not be available for other functions. Cells that do not take up
glucose in sufficient amounts will shrink as a result of extracellular
hyperosmolarity. The functions of lymphocytes that have shrunk are impaired
(e.g., the formation of superoxides, which are important for immune defense).
Diabetics are thus more prone to infection, for example, of the skin (boils) or
kidney (pyelonephritis). These infections, in turn, increase the demand for
insulin, because they lead to an increased release of insulin-antagonistic
hormones. Hyperglycemia promotes the formation of sugar-containing plasma
proteins such as fibrinogen, haptoglobin, 2-macroglobulin as well as clotting
factors VVIII. In this way clotting tendency and blood viscosity may be increased
and thus the risk of thrombosis raised.
By binding of glucose to free amino-groups of proteins and a subsequent, not
fully understood, irreversible Amadori reaction, advanced glycation end products
AGEs) are formed. They also occur in increasing amounts in the elderly. A protein
network can be formed through the formation of pentosin. AGEs bind to
respective receptors of the cell membrane and can thus promote the deposition
of col lagenin the basement membranes of the blood vessels. The formation of
connective tissue is in part stimulated via transforming growth factor (TGF-).
Additionally, however, the collagen fibers can be changed by glycosylation. Both
changes produce thickening of the basement membranes with reduced
permeability and luminal narrowing (microangiopathy). Changes occur in the
retina, also as a result of microangiopathies, that ultimately may lead to
blindness (retinopathy). In the kidney glomerulosclerosis (KimmelstielWilson)
develops, which can result in proteinuria, reduced glomerular filtration rate due
to a loss of glomeruli, hypertension, and renal failure. Because of the high amino
acid concentration in plasma, hyperfiltration takes place in the remaining intact
glomeruli, which as a result are also damaged. Together with a rise of VLDL in
blood and the raised clotting tendency of the blood (see above), hypertension
promotes the development of a macroangiopathy that can further damage the
kidneys and cause myocardial infarction, cerebral infarction, and peripheral
vascular disease. Lastly, glucose can react with hemoglobin (HbA) to form HbA
1c, whose increased concentration inblood points to a hyperglycemia that has
been present for some time. HbA 1c has a higher oxygen affinity than HbA and
thus releases oxygen in the periphery less readily. The persisting insulin
deficiency further leads to a reduction in the erythrocytic concentration of 2,3bisphosphoglycerate (BPG), which, as allosteric regulator of hemoglobin, reduces
its oxygen affinity. The BPG deficiency also results in an increased oxygen affinity
of HbA. Diabetic mothers have a statistically higher chance of giving birth to a
heavier than normal baby. This may be the result of an increased concentration
of amino acids in blood, producing an increased release of somatotropin.
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Clinical manifestations of DM
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Atherosclerosis due to DM
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Diabetic retinopathy
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Diabetic nephropathy
CLINICAL PATHOPHYSIOLOGY OF THYROID GLAND
Hyperfunction of thyroid gland is designated by the term thyrotoxicosis or
hyperthyrosis.
The reasons of hyperthyrosis can be the following:
1. Central disturbances increase of thyroliberin and thyrotropic hormone (H)
secretion.
2. Strictly glandular disturbances (primary hyperthyrosis). The most widespread
clinical forms of primary hyperthyrosis are:
) Diffuse toxic goiter (Bazeds disease, Graves disease, Parris disease);
b) Toxic adenoma of thyroid gland;
c) Nodular goiter.
The most often reason of development hyperthyrosis is diffuse toxic goiter.
Consider that diffuse toxic goiter is autoimmune disease, in which occurrence
matter are thyroid-stimulating antibodies which like H are capable to contact
with receptors on basal membrane of thyrocyte, that results in cell activation.
3. Peripheral disorders :
) Increase of cell sensitivity to action of 3 and 4;
b) Decrease of binding of thyroid hormonees by transport proteins;
c) Decrease of thyroid hormonees metabolism in liver in its insufficiency.
The starting mechanism of diffuse toxic goiter occurrence in patients with
hereditary defect of immune system can be psychoemotional stress or virus
which is forming in thyrocyte membrane complex, on which the antibodies will
be derivated.
Main manifestations of diffuse toxic goiter:
) goiter (increase of thyroid gland)
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Goiter
Hypothyrosis
In a basis of hypofunction of thyroid gland the following reasons can be.
1. Central disorders: decrease of formation both secretion of thyreoliberine and
thyreotropic hormone (H).
2. Gland disorders , which result in development primary hypothyrosis:
a) destruction of a gland tissue, for example, radioactive iod;
b) deficiency of iod drinking water and food endemic goiter;
c) autoimmune damage of gland cells autoimmune thyroiditis of
Chaschimoto;
d) inherent disorders hypo- and aplasia of thyroid gland, enzymopathy.
3. Peripheral disorders:
) nonsensitivity of peripheral cells for action of thyroid hormones;
b) increased binding of thyroid hormones with plasma proteins of blood;
c) strengthened metabolism in liver.
In development of manifestations of hypothyrosis the following mechanisms.
k) lethargy , sleepiness;
l) mental disturbance loss of memory, stupidity, absence of alive interests;
m) decrease of metabolism.