Pancreatic hormone preparations. The biological role of pancreatic hormones
Major pancreatic hormones:
Insulin (normal concentration in the blood in a healthy person is 3-25 mcU / ml, in children 3-20 mcU / ml, in pregnant women and the elderly 6-27 mcU / ml);
glucagon (plasma concentration 27-120 pg/ml);
c-peptide (normal level 0.5-3.0 ng/ml);
· pancreatic polypeptide (the level of PP in fasting serum is 80 pg/ml);
gastrin (norm from 0 to 200 pg / ml in blood serum);
amylin;
The main function of insulin in the body is to lower blood sugar levels. This happens due to the simultaneous action in several directions. Insulin stops the formation of glucose in the liver, increasing the amount of sugar absorbed by the tissues of our body due to the permeability of cell membranes. And at the same time, this hormone stops the breakdown of glucagon, which is part of a polymer chain consisting of glucose molecules.
The alpha cells of the islets of Langerhans are responsible for the production of glucagon. Glucagon is responsible for increasing the amount of glucose in the bloodstream by stimulating its formation in the liver. In addition, glucagon promotes the breakdown of lipids in adipose tissue.
A growth hormone growth hormone increases the activity of alpha cells. In contrast, the delta cell hormone somatostatin inhibits the formation and secretion of glucagon, as it blocks the entry into alpha cells of Ca ions, which are necessary for the formation and secretion of glucagon.
Physiological significance lipocaine. It promotes the utilization of fats by stimulating the formation of lipids and the oxidation of fatty acids in the liver, it prevents fatty degeneration of the liver.
Functions vagotonin- increased tone of the vagus nerves, increased their activity.
Functions centropnein- excitation of the respiratory center, promoting relaxation of the smooth muscles of the bronchi, increasing the ability of hemoglobin to bind oxygen, improving oxygen transport.
The human pancreas, mainly in its caudal part, contains approximately 2 million islets of Langerhans, which make up 1% of its mass. The islets are made up of alpha, beta, and delta cells that secrete glucagon, insulin, and somatostatin (which inhibit growth hormone secretion), respectively.
Insulin Normally, it is the main regulator of blood glucose levels. Even a slight increase in blood glucose causes the secretion of insulin and stimulates its further synthesis by beta cells.
The mechanism of action of insulin is due to the fact that homon enhances the uptake of glucose by tissues and promotes its conversion into glycogen. Insulin, by increasing the permeability of cell membranes for glucose and lowering the tissue threshold to it, facilitates the penetration of glucose into cells. In addition to stimulating the transport of glucose into the cell, insulin stimulates the transport of amino acids and potassium into the cell.
Cells are very permeable to glucose; in them, insulin increases the concentration of glucokinase and glycogen synthetase, which leads to the accumulation and deposition of glucose in the liver in the form of glycogen. In addition to hepatocytes, glycogen depots are also striated muscle cells.
CLASSIFICATION OF INSULIN DRUGS
All insulin preparations manufactured by global pharmaceutical companies differ mainly in three main features:
1) by origin;
2) by the speed of onset of effects and their duration;
3) according to the method of purification and the degree of purity of preparations.
I. By origin, they distinguish:
a) natural (biosynthetic), natural, insulin preparations made from the pancreas of cattle, for example, insulin tape GPP, ultralente MS, and more often pigs (for example, actrapid, insulrap SPP, monotard MS, semilente, etc.);
b) synthetic or, more precisely, species-specific, human insulins. These drugs are obtained using genetic engineering methods by DNA recombinant technology, and therefore they are most often called DNA recombinant insulin preparations (actrapid NM, homofan, isophane NM, humulin, ultratard NM, monotard NM, etc.).
III. According to the speed of onset of effects and their duration, there are:
a) quick short-acting drugs (actrapid, actrapid MS, actrapid NM, insulrap, homorap 40, insuman rapid, etc.). The onset of action of these drugs is after 15-30 minutes, the duration of action is 6-8 hours;
b) drugs of medium duration of action (onset of action after 1-2 hours, the total duration of the effect is 12-16 hours); - Semilente MS; - humulin N, humulin tape, homofan; - tape, tape MC, monotard MC (2-4 hours and 20-24 hours, respectively); - iletin I NPH, iletin II NPH; - insulong SPP, insulin tape GPP, SPP, etc.
c) drugs of medium duration mixed with short-acting insulin: (onset of action 30 minutes; duration - from 10 to 24 hours);
Aktrafan NM;
Humulin M-1; M-2; M-3; M-4 (duration of action up to 12-16 hours);
Insuman comb. 15/85; 25/75; 50/50 (valid for 10-16 hours).
d) long-acting drugs:
Ultratape, ultratape MS, ultratape HM (up to 28 hours);
Insulin Superlente SPP (up to 28 hours);
Humulin ultralente, ultratard HM (up to 24-28 hours).
Actrapid, derived from the beta cells of the porcine pancreatic islets, is available as an official drug in 10 ml vials, most often with an activity of 40 IU per 1 ml. It is administered parenterally, most often under the skin. This drug has a rapid hypoglycemic effect. The effect develops after 15-20 minutes, and the peak of action is noted after 2-4 hours. The total duration of the hypoglycemic effect is 6-8 hours in adults, and in children up to 8-10 hours.
Advantages of fast short-acting insulin preparations (Actrapida):
1) act quickly;
2) give a physiological peak in blood concentration;
3) are short-lived.
Indications for the use of rapid short-acting insulin preparations:
1. Treatment of patients with insulin-dependent diabetes mellitus. The drug is injected under the skin.
2. In the most severe forms of non-insulin dependent diabetes mellitus in adults.
3. With diabetic (hyperglycemic) coma. In this case, the drugs are administered both under the skin and into a vein.
ANTI-DIABETIC (HYPOGLYCEMIC) ORAL MEDICINES
Stimulating the secretion of endogenous insulin (sulfonylurea drugs):
1. First generation drugs:
a) chlorpropamide (syn.: diabinez, katanil, etc.);
b) bukarban (syn.: oranil, etc.);
c) butamide (syn.: orabet, etc.);
d) tolinase.
2. Second generation drugs:
a) glibenclamide (syn.: maninil, oramide, etc.);
b) glipizide (syn.: minidiab, glibinez);
c) gliquidone (syn.: glurenorm);
d) gliclazide (synonym: predian, diabeton).
II. Influencing the metabolism and absorption of glucose (biguanides):
a) buformin (glibutide, adebit, silbine retard, dimethyl biguanide);
b) metformin (gliformin). III. Inhibiting glucose absorption:
a) glucobay (acarbose);
b) guarem (guar gum).
BUTAMIDE (Butamidum; issue in tab. 0.25 and 0.5) is a first-generation drug, a sulfonylurea derivative. The mechanism of its action is associated with a stimulating effect on pancreatic beta cells and their increased secretion of insulin. The onset of action is 30 minutes, its duration is 12 hours. Assign the drug 1-2 times a day. Butamide is excreted by the kidneys. This drug is well tolerated.
Side effects:
1. Dyspepsia. 2. Allergy. 3. Leukocytopenia, thrombocytopenia. 4. Hepatotoxicity. 5. Development of tolerance is possible.
BIGUANIDES are derivatives of guanidine. The two best known are:
Buformin (glibutide, adebite);
Metformin.
GLIBUTID (Glibutidum; issue in tab. 0.05)
1) promotes the absorption of glucose by muscles in which lactic acid accumulates; 2) increases lipolysis; 3) reduces appetite and body weight; 4) normalizes protein metabolism (in this regard, the drug is prescribed for overweight).
Most often they are used in patients with DM-II, accompanied by obesity.
The pancreas produces several hormones:
glucagon, insulin, somatostatin, gastrin.
Of them insulin is of the greatest practical importance.
Insulin is produced in- cells of the islets of Langerhans.
The cells of the pancreas constantly release a small basal amount of insulin.
In response to various stimuli (especially glucose), insulin production is greatly increased.
Lack of insulin or excess of factors that counteract its activity,
lead to the development diabetes - severe illness
which is characterized by:
high blood glucose (hyperglycemia)
its excretion in the urine (concentrations in the primary urine exceed the possibilities
subsequent reabsorption - glycosuria)
accumulation of products of impaired fat metabolism - acetone, hydroxybutyric acid -
in the blood with intoxication and the development of acidosis (ketoacidosis)
excreted in the urine (ketonuria)
progressive damage to the capillaries of the kidneys
and retina (retinopathy)
nervous tissue
generalized atherosclerosis
Mechanism of action of insulin:
1, Receptor binding
Cell membranes have specific receptors for insulin.
interacting with which the hormone several times enhances their absorption of glucose.
It is important for tissues that receive very little glucose without insulin (muscle, fat).
The supply of glucose to organs that are sufficiently supplied with it without insulin (liver, brain, kidneys) also increases.
2. Membrane entry of glucose transport protein
As a result of the binding of the hormone to the receptor, the enzyme part of the receptor (tyrosine kinase) is activated.
Tyrosine kinase activates other enzymes of metabolism in the cell and the entry of a glucose carrier protein from the depot into the membrane.
3. The insulin-receptor complex enters the cell and activates the work of ribosomes
(protein synthesis) and genetic apparatus.
4. As a result, anabolic processes are enhanced in the cell and catabolic ones are inhibited.
Effects of insulin
Generally has anabolic and anti-catabolic effects
carbohydrate metabolism
Accelerate the transport of glucose through the cytolemma into cells
Inhibit gluconeogenesis
(conversion of amino acids to glucose)
Accelerate the formation of glycogen
(activates glucokinase and glycogen synthetase) and
inhibits glycogenolysis (inhibits phosphorylase)
Fat metabolism
Inhibits lipolysis (suppresses lipase activity)
Increases the synthesis of fatty acids,
accelerates their esterification
Inhibits the conversion of fatty acids and amino acids
into keto acids
Protein metabolism
Accelerates the transport of amino acids into the cell, increases protein synthesis and cell growth
Action of insulin:
On the liver
- increased glucose storage in the form of glycogen
inhibition of glycogenolysis,
ketogenesis,
gluconeogenesis
(this is partly ensured by increased transport of glucose into cells and its phosphorylation)
on skeletal muscles
- activation of protein synthesis due to
enhancing the transport of amino acids and increasing ribosomal activity,
- activation of glycogen synthesis,
expended during muscular work
(due to increased glucose transport).
on adipose tissue
Increased deposition of triglycerides
(the most efficient form of energy conservation in the body)
by reducing lipolysis and stimulating the esterification of fatty acids.
Symptoms: thirst (polydipsia)
increased diuresis (polyuria)
increased appetite (polyphagia)
weakness
weight loss
angiopathy
visual impairment, etc.
Etiological classification of glycemic disorders (WHO, 1999)
| Characteristic |
|
| diabetes mellitus type 1 | Destructionβ -cells leading to absolute insufficiency insulin: autoimmune (90%) and idiopathic (10%) |
| diabetes mellitus type 2 | From p preferential insulin resistance and hyperinsulinemia with relative insulin insufficiency to a predominant secretory defect with or without relative insulin resistance |
| Other specific types of diabetes | Genetic defects in β-cell function Diseases of the exocrine pancreas Endocrinopathy Diabetes induced by drugs, chemicals (alloxan, nitrophenylurea (rat poison), hydrogencyanide, etc.) infections Unusual forms of insulin-mediated diabetes Other genetic syndromes sometimes associated with diabetes |
| Gestational diabetes | Diabetes only during pregnancy |
The result of insulin - multilateral positive exchange shifts:
Activation of carbohydrate metabolism.
Increased transport of glucose into cells
Increased use of glucose in the tricarboxylic acid cycle and supply of glycerophosphate Increased conversion of glucose to glycogen
Inhibition of gluconeogenesis
Decrease in blood sugar levels - cessation of glucosuria.
Transformation of fat metabolism towards lipogenesis.
Activation of the formation of triglycerides from free fatty acids
as a result of glucose entering the adipose tissue and the formation of glycerophosphate
Decreased levels of free fatty acids in the blood and
a decrease in their conversion in the liver into ketone bodies - the elimination of ketoacidosis.
Reducing the formation of cholesterol in the liver.
responsible for the development of diabetogenic atherosclerosis
Due to increased lipogenesis, body weight increases.
Changes in protein metabolism.
Saving the fund of amino acids due to the inhibition of gluconeogenesis
Activation of RNA synthesis
Stimulation of synthesis and inhibition of protein breakdown.
Diabetes treatment:
per molecule of insulin Nobel Prize awarded twice:
In 1923 - for its discovery (Frederick Banting and John Macleod)
In 1958 - for the establishment of the chemical composition (Frederick Senger)
The unthinkable speed of putting the discovery into practice:
It took only 3 months from a brilliant insight to testing the effect of the drug on dogs with a removed pancreas.
After 8 months, the first patient was treated with insulin,
After 2 years, pharmaceutical companies could provide them to everyone.
hungry diet .
Banting and Best.
WordBantingin English became common knowledge 60 years before the discovery of insulin - thanks to William Banting, an undertaker and an exorbitant fat man.
On St. James Street in London, his house, sign and staircase are still preserved.
On this ladder one day Banting could not go down, he was so fat.
Then he went on a starvation diet.
Banting outlined his experience of losing weight in the pamphlet "Letter on Obesity to the Public." The book was published in 1863 and became an instant bestseller.
His system became so popular that the word "banting" in English has acquired the meaning of "starvation diet".
For the English-speaking public, the message about the discovery of insulin by scientists named Banting and Best sounded like a pun: Banting and Best - Starvation Diet and Best.
Before the beginning of the twentieth century weakness, fatigue, constant thirst, diabetes (up to 20 liters of urine per day), non-healing ulcers at the site of the slightest wound, etc., caused by diabetes, could be prolonged by the only empirically found method - to starve.
With type 2 diabetes, this helped for quite a long time, with type 1 - for several years.
Cause of diabetes became somewhat clear in 1674,
when the London doctor Thomas Willis tasted the patient's urine.
It turned out to be sweet due to the fact that the body got rid of sugar by any means.
Relationship between diabetes and pancreatic dysfunction discovered in the middle of the nineteenth century.
Leonid Vasilyevich Sobolev
In 1900-1901, he formulated the principles for obtaining insulin.
Blood sugar levels are regulated by the pancreatic islets of Langerhans. –
suggested in 1916 by the English physiologist Sharpy-Schafer.
The main thing remained to isolate insulin from the pancreas of animals and apply it to the treatment of humans.
The first to succeed was a Canadian doctor Fred Bunting .
Banting took up the problem of diabetes without work experience and serious scientific training.
Directly from his parent's farm, he entered the University of Toronto.
Then he served in the army, worked as a surgeon in a field hospital, was seriously wounded.
After demobilization, Banting took a position as an assistant professor of anatomy and physiology at the University of Toronto.
He immediately suggested to the head of the department professor John McLeod engage in the secretion of pancreatic hormone.
McLeod, a prominent specialist in the field of diabetes, was well aware of how many famous scientists had been unsuccessfully struggling with this problem for decades, so he turned down the offer.
But a few months later, Banting came up with an idea that hit him at 2 am in April 1921:
ligate the ducts of the pancreas so that it stops producing trypsin.
The idea turned out to be correct, because. trypsin ceased to break down the protein molecules of insulin, and insulin became possible to isolate.
McLeod left for Scotland and allowed Banting to use his laboratory for 2 months, to set up experiments at his own expense. Even singled out as a student assistant Charles Best.
Best knew how to masterfully determine the concentration of sugar in the blood and urine.
To raise funds, Banting sold all his property, but the proceeds were not enough to get the first results.
After 2 months, the professor returned and almost kicked Banting and Best out of the laboratory.
But, having figured out what the researchers managed to achieve, he immediately connected the entire department with himself at the head.
Banting did not apply for a patent.
The developers first tried the drug on themselves - according to the custom of the then doctors.
The rules were simple then, and diabetics were dying, so improvements in isolation and purification methods were carried out in parallel with clinical application.
They took the risk of injecting the boy, who was to die in a few days.
The attempt was unsuccessful - the crude extract of the pancreas did not work
But after 3 weeks January 23, 1922 After an injection of poorly purified insulin, 14-year-old Leonard Thompson's blood sugar levels dropped.
Among Banting's first patients was a friend of his, also a physician.
Another patient, a teenage girl, was brought from the US to Canada by her doctor mother.
The girl was given an injection right at the station, she was already in a coma.
After she came to, the girl, receiving insulin, lived for another 60 years.
The industrial production of insulin was started by a doctor whose wife, an endocrinologist, had diabetes, Dane August Krogh ( Novo Nordisk is a Danish company that is still one of the largest manufacturers of insulin).
Banting shared his prizes equally with Best, and McLeod with Collip (biochemist).
In Canada, Bunting became a national hero.
In 1923 University of Toronto(7 years after his graduation from Banting) awarded him the degree of Doctor of Science, elected him a professor and opened a new department - specifically to continue his work.
Canadian Parliament gave him an annual pension.
In 1930 Banting became director of the research banting and best institute, was elected a member Royal Society of London, received knighthood of Great Britain.
With the beginning of the 2nd World War, he went to the front as a volunteer, organizer of medical care.
On February 22, 1941, Banting died when the plane in which he was flying crashed over the snowy desert of Newfoundland.
Monuments to Banting stand in Canada at home and at the place of his death.
November 14 - Banting's birthday is celebrated as anti-diabetes day .
Insulin preparations
At ultra-short action
Lizpro (Humalog)
Beginning of action after 15 minutes, duration 4 hours, taken before meals.
Regular crystalline insulin (obsolete)
actrapid MK, MP (pork), actrapid H , ilitin R (regular), humulin R
Beginning of action after 30 minutes, duration 6 hours, taken 30 minutes before meals.
intermediate action
Semilente MK
Beginning of action after 1 hour, duration 10 hours, taken one hour before meals.
Lente, Lente MK
Beginning of action after 2 hours, duration 24 hours, taken 2 hours before meals.
Homofan, protofan H , monotard H , MK
Beginning of action after 45 minutes, duration 20 hours, taken 45 minutes before meals.
prolonged action
Ultralente MK
Beginning of action after 2 hours, duration 30 hours, taken 1.5 hours before meals.
Ultralente iletin
Beginning of action after 8 hours, duration 25 hours, taken 2 hours before meals.
Ultratard H
Humulin U
Beginning of action after 3 hours, duration 25 hours, taken 3 hours before meals.
Short acting drugs:
Injection - subcutaneously or (with hyperglycemic coma) intravenously
Disadvantages - high activity at the peak of action (which creates the risk of hypoglycemic coma), short duration of action.
Intermediate drugs:
They are used in the treatment of compensated diabetes, after treatment with short-acting drugs with the determination of insulin sensitivity.
Long acting drugs:
They are administered only subcutaneously.
A combination of drugs with a short and medium duration of action is advisable.
MP - monopeak: purified by gel filtration.
MK - monocomponent: purified by molecular sieve and ion-exchange chromatography (the best degree of purification).
Bovine insulin differs from human in 3 amino acids, greater antigenic activity.
pork insulin differs from the human by only one amino acid.
human insulin obtained by recombinant DNA technology (by placing DNA in a yeast cell and hydrolyzing the accumulated proinsulin to an insulin molecule).
Insulin delivery systems :
Infusion systems.
Portable pumps.
Implantable autoinjector
A titanium reservoir is implanted with a supply of insulin for 21 days.
It is surrounded by a reservoir filled with gaseous fluorocarbon.
A titanium reservoir catheter is connected to a blood vessel.
Under the influence of heat, the gas expands and provides a continuous supply of insulin to the blood.
nasal spray
In the fall of 2005, the US Food and Drug Administration approved the first insulin nasal spray.
Regular injections of insulin
Dosing insulin : strictly individual.
The optimal dose should reduce blood glucose levels to normal, eliminate glucosuria and other symptoms of diabetes.
Areas of subcutaneous injections (different suction rates): anterior abdominal wall, outer shoulders, anterior outer thighs, buttocks.
Short acting drugs- in the abdomen (faster absorption),
Long acting drugs- in the thighs or buttocks.
The shoulders are uncomfortable for independent injections.
The effectiveness of therapy is controlled through
Systematic determination of "hungry" blood sugar levels and
Its excretion with urine per day
The best treatment option for type 1 diabetes is
A multiple insulin injection regimen that mimics physiological insulin secretion.
Under physiological conditions
basal (background) secretion of insulin occurs continuously and is 1 unit of insulin per hour.
During physical activity insulin secretion normally decreases.
While eating
Additional (stimulated) insulin secretion is required (1-2 units per 10 g of carbohydrates).
This complex secretion of insulin can be mimicked as follows:
Before each meal, short-acting drugs are administered.
Basal secretion is supported by long-acting drugs.
Complications of insulin therapy:
hypoglycemia
As a result
Untimely food intake
Unusual physical activity
The introduction of an unreasonably high dose of insulin.
Manifested
dizzy,
Tremor
Weakness
Hypoglycemic coma
Perhaps the development of insulin shock, loss of consciousness, death.
docked taking glucose.
Complications of diabetes
diabetic coma
Due to
Insufficient doses of insulin
diet violations,
stressful situations.
Without immediate intensive care, diabetic coma (accompanied by cerebral edema)
always leads to death.
As a result
Increasing CNS intoxication with ketone bodies,
ammonia,
acidotic shift
emergency therapy held intravenous administration of insulin.
Under the influence of a large dose of insulin into cells along with glucose includes potassium
(liver, skeletal muscle)
The concentration of potassium in the blood drops sharply. The result is heart failure.
Immune disorders.
Insulin allergy, immune resistance to insulin.
Lipodystrophy at the injection site.
Parathyroidin- the drug of the parathyroid hormone parathyrin (parathormone), has recently been used very rarely, since there are more effective means. The regulation of the production of this hormone depends on the amount of Ca 2+ in the blood. The pituitary gland does not affect the synthesis of parathyrin.
Pharmacological is to regulate the exchange of calcium and phosphorus. Its target organs are bones and kidneys, which have specific membrane receptors for parathyrin. In the intestine, parathyrin activates the absorption of calcium and inorganic phosphate. It is believed that the stimulating effect on calcium absorption in the intestine is not associated with the direct influence of parathyrin, but with an increase in formation under its influence. calcitriol (active form of calciferol in the kidneys). In the renal tubules, parathyrin increases calcium reabsorption and decreases phosphate reabsorption. At the same time, in accordance with the content of phosphorus in the blood decreases, while the level of calcium increases.
Normal levels of parathyrin have an anabolic (osteoplastic) effect with increased bone growth and mineralization. With hyperfunction of the parathyroid glands, osteoporosis occurs, hyperplasia of fibrous tissue, which leads to deformation of the bones, their fractures. In cases of overproduction of parathyrin, calcitonin which prevents calcium from being washed out of the bone tissue.
Indications: hypoparathyroidism, to prevent tetany due to hypocalcemia (in acute cases, intravenous calcium preparations or their combination with parathyroid hormone preparations should be administered).
Contraindications: increased calcium in the blood, with diseases of the heart, kidneys, allergic diathesis.
Dihydrotachysterol (takhistin) - chemically close to ergocalciferol (vitamin D2). Increases the absorption of calcium in the intestines, at the same time - the excretion of phosphorus in the urine. Unlike ergocalciferol, there is no D-vitamin activity.
Indications: disorders of phosphorus-calcium metabolism, including hypocalcic convulsions, spasmophilia, allergic reactions, hypoparathyroidism.
Contraindications: increased calcium in the blood.
Side effect: nausea.
Hormonal preparations of the pancreas.
insulin preparations
In the regulation of metabolic processes in the body, pancreatic hormones are of great importance. AT β-cells pancreatic islets are synthesized insulin, which has a pronounced hypoglycemic effect, in a-cells produced contrainsular hormone glucagon, which has a hyperglycemic effect. Besides, δ-clitite pancreas produce somatostatin .
Insufficient insulin secretion leads to diabetes mellitus (DM). diabetes mellitus - a disease that occupies one of the dramatic pages of world medicine. According to WHO, the number of patients with diabetes worldwide in 2000 was 151 million people by 2010 is expected to increase to 221 million people, and by 2025 - 330 million people, which suggests its global epidemic. DM causes the earliest of all diseases disability, high mortality, frequent blindness, kidney failure, and is also a risk factor for cardiovascular disease. Diabetes ranks first among endocrine diseases. The United Nations has declared SD a pandemic of the 21st century.
According to the WHO classification (1999.) There are two main types of the disease - type 1 and type 2 diabetes(according to insulin-dependent and non-insulin-dependent diabetes). Moreover, an increase in the number of patients is predicted mainly due to patients with type 2 diabetes, which currently account for 85-90% of the total number of patients with diabetes. This type of DM is diagnosed 10 times more often than type 1 DM.
Diabetes is treated with diet, insulin preparations, and oral antidiabetic drugs. Effective treatment of patients with CD should provide approximately the same basal insulin level throughout the day and prevent hyperglycemia that occurs after eating (postprandial glycemia).
The main and only objective indicator of the effectiveness of DM therapy, reflecting the state of compensation for the disease, is the level of glycated hemoglobin (HbA1C or A1C). HbA1c or A1C - hemoglobin, which is covalently linked to glucose and is an indicator of the level of glycemia for the previous 2-3 months. Its level correlates well with the values of blood glucose levels and the likelihood of complications of diabetes. A 1% decrease in glycosylated hemoglobin is accompanied by a 35% decrease in the risk of developing complications of diabetes (regardless of the initial level of HbA1c).
The basis of the treatment of CD is properly selected hypoglycemic therapy.
History reference. The principles for obtaining insulin were developed by L. V. Sobolev (in 1901), who, in an experiment on the glands of newborn calves (they still do not have trypsin, decomposes insulin), showed that pancreatic islets (Langerhans) are the substrate of the internal secretion of the pancreas. In 1921, Canadian scientists F. G. Banting and C. X. Best isolated pure insulin and developed a method for industrial production. After 33 years, Sanger and his co-workers deciphered the primary structure of bovine insulin, for which they received the Nobel Prize.
The creation of insulin preparations took place in several stages:
First generation insulins - porcine and bovine (bovine) insulin;
Second generation insulins - monopic and monocomponent insulins (50s of the XX century)
Third generation insulins - semi-synthetic and genetically engineered insulin (80s of the XX century)
Obtaining insulin analogs and inhaled insulin (late XX - early XXI century).
Animal insulins differed from human insulin in amino acid composition: bovine insulin - in amino acids in three positions, pork - in one position (position 30 in chain B). Immunological adverse reactions occurred more frequently with bovine insulin than with porcine or human insulin. These reactions were expressed in the development of immunological resistance and allergy to insulin.
To reduce the immunological properties of insulin preparations, special purification methods have been developed, which made it possible to obtain a second generation. First there were monopeak insulins obtained by gel chromatography. Later it was found that they contain a small amount of impurities of insulin-like peptides. The next step was the creation of monocomponent insulins (UA-insulins), which were obtained by additional purification using ion exchange chromatography. With the use of monocomponent porcine insulins, the production of antibodies and the development of local reactions in patients were rare (now bovine and monopic porcine insulins are not used in Ukraine).
Human insulin preparations are obtained either by a semi-synthetic method using an enzymatic-chemical substitution at position B30 in porcine insulin of the amino acid alanine for threonine, or by a biosynthetic method using genetic engineering technology. Practice has shown that there is no significant clinical difference between human insulin and high-quality monocomponent porcine insulin.
Now work continues on improving and searching for new forms of insulin.
According to the chemical structure, insulin is a protein, the molecule of which consists of 51 amino acids, forming two polypeptide chains connected by two disulfide bridges. In the physiological regulation of insulin synthesis, the dominant role is played by the concentration glucose in blood. Penetrating into β-cells, glucose is metabolized and contributes to an increase in the intracellular ATP content. The latter, by blocking ATP-dependent potassium channels, causes depolarization of the cell membrane. This facilitates the penetration of calcium ions into β-cells (through voltage-gated calcium channels that have opened) and the release of insulin by exocytosis. In addition, insulin secretion is affected by amino acids, free fatty acids, glucagon, secretin, electrolytes (especially Ca 2+), the autonomic nervous system (the sympathetic nervous system is inhibitory, and the parasympathetic nervous system is stimulating).
Pharmacodynamics. The action of insulin is aimed at the metabolism of carbohydrates, proteins, fats, minerals. The main thing in the action of insulin is its regulatory effect on the metabolism of carbohydrates, lowering the content of glucose in the blood. This is achieved by the fact that insulin promotes the active transport of glucose and other hexoses, as well as pentoses through cell membranes and their utilization by the liver, muscle and adipose tissues. Insulin stimulates glycolysis, induces the synthesis of the enzymes glucokinase, phosphofructokinase and pyruvate kinase, stimulates the pentose phosphate cycle by activating glucose-6-phosphate dehydrogenase, increases glycogen synthesis by activating glycogen synthetase, the activity of which is reduced in patients with diabetes. On the other hand, the hormone inhibits glycogenolysis (decomposition of glycogen) and gluconeogenesis.
Insulin plays an important role in stimulating nucleotide biosynthesis, increasing the content of 3,5 nucleotases, nucleoside triphosphatase, including in the nuclear envelope, where it regulates the transport of mRNA from the nucleus to the cytoplasm. Insulin stimulates the biosynthesis of nucleic acids and proteins. In parallel to the enhancement of anabolic processes, insulin inhibits the catabolic reactions of the breakdown of protein molecules. It also stimulates the processes of lipogenesis, the formation of glycerol, its introduction into lipids. Along with the synthesis of triglycerides, insulin activates the synthesis of phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and cardiolipin) in fat cells, and also stimulates the biosynthesis of cholesterol, which, like phospholipids and some glycoproteins, is necessary for building cell membranes.
With an insufficient amount of insulin, lipogenesis is suppressed, lipogenesis increases, lipid peroxidation in the blood and urine increases the level of ketone bodies. Due to the reduced activity of lipoprotein lipase in the blood, the concentration of β-lipoproteins increases, which are essential in the development of atherosclerosis. Insulin prevents the body from losing fluid and K+ in the urine.
The essence of the molecular mechanism of action of insulin on intracellular processes is not fully disclosed. However, the first step in the action of insulin is binding to specific receptors on the plasma membrane of target cells, primarily in the liver, adipose tissue and muscles.
Insulin binds to the α-subunit of the receptor (contains the main insulin-binding domain). At the same time, the kinase activity of the β-subunit of the receptor (Tyrosine kinase) is stimulated, it is autophosphorylated. An "insulin + receptor" complex is created, which penetrates into the cell by endocytosis, where insulin is released and the cellular mechanisms of the hormone's action are triggered.
In the cellular mechanisms of insulin action, not only secondary messengers take part: cAMP, Ca 2+, calcium-calmodulin complex, inositol triphosphate, diacylglycerol, but also fructose-2,6-diphosphate, which is called the third mediator of insulin in its effect on intracellular biochemical processes. It is the growth under the influence of insulin of the level of fructose-2,6-diphosphate that promotes the utilization of glucose from the blood, the formation of fats from it.
The number of receptors and their ability to bind is influenced by a number of factors. In particular, the number of receptors is reduced in cases of obesity, non-insulin dependent type 2 diabetes, and peripheral hyperinsulinism.
Insulin receptors exist not only on the plasma membrane, but also in the membrane components of such internal organelles as the nucleus, endoplasmic reticulum, Golgi complex. The introduction of insulin to patients with diabetes helps to reduce the level of glucose in the blood and the accumulation of glycogen in tissues, reduce glucosuria and associated polyuria, polydipsia.
Due to the normalization of protein metabolism, the concentration of nitrogen compounds in the urine decreases, and as a result of the normalization of fat metabolism, ketone bodies - acetone, acetoacetic and hydroxybutyric acids - disappear from the blood and urine. Weight loss stops and excessive feeling of hunger disappears ( bulimia ). The detoxification function of the liver increases, the body's resistance to infections increases.
Classification. Modern insulin preparations differ from each other speed and duration of action. They can be divided into the following groups:
1. Short-acting insulin preparations, or simple insulins ( actrapid MK , humulin etc.) The decrease in blood glucose levels after their subcutaneous injection begins after 15-30 minutes, the maximum effect is observed after 1.5-3 hours, the effect lasts 6-8 hours.
Significant advances in the study of molecular structure, biological activity and therapeutic properties have led to the modification of the human insulin formula and the development of short-acting insulin analogues.
The first analogue lisproinsulin (humalog) is identical to human insulin except for the position of lysine and proline at positions 28 and 29 of the B chain. Such a change did not affect the activity of the A-chain, but reduced the processes of self-association of insulin molecules and ensured an acceleration of absorption from the subcutaneous depot. After the injection, the onset of action is after 5-15 minutes, reaching a peak after 30-90 minutes, the duration of action is 3-4 hours.
The second analogue aspart(tradename - novo-rapid) modified by replacing one amino acid in position B-28 (proline) with aspartic acid, reduces the phenomenon of cell self-aggregation of insulin molecules into dimmers and hexamers and accelerates its absorption.
The third analogue - glulisin(tradename epaidra) is practically similar to endogenous human insulin and biosynthetic regular human insulin with certain structural changes in the formula. Thus, in the 33 position, asparagine is replaced by lysine, and the lysine in position B29 is replaced by glutamic acid. By stimulating the peripheral use of glucose by skeletal muscles and adipose tissue, inhibiting gluconeogenesis in the liver, glulisin (epaidra) improves glycemic control, also inhibits lipolysis and proteolysis, accelerates protein synthesis, activates insulin receptors and its substrates, and is fully consistent with the effect of regular human insulin on these elements.
2. Long-acting insulin preparations:
2.1. medium duration (The onset of action after subcutaneous administration is 1.5-2 hours, duration 8-12 hours). These drugs are also called insulin semilente. This group includes insulins on neutral Protamine Hagedorn: B-insulin, Monodar B, Farmasulin HNP. Since insulin and protamine are included in HNP-insulin in equal, isophaneous, ratios, they are also called isophane insulins;
2.2. Long acting (ultralente) with onset of action after 6-8 hours, duration of action 20-30 hours. These include insulin preparations containing Zn2 + in their composition: suspension-insulin-ultralente, Farmasulin HL. Long-acting drugs are administered only subcutaneously or intramuscularly.
3. Combined preparations containing standard mixtures of group 1 drugs with NPH-insulins in different ratios of groups 1 and 2: 30/70, 20/80,10/90, etc. - Monodar K ZO, Farmasulin 30/70 m. Some drugs are available in special syringe tubes.
To achieve maximum glycemic control in diabetic patients, an insulin regimen is needed that fully mimics the physiological profile of insulin during the day. Long-acting insulins have their drawbacks, in particular, the presence of a peak effect 5-7 hours after the administration of the drug leads to the development of hypoglycemia, especially at night. These shortcomings have led to the development of insulin analogues with pharmacokinetic properties of effective basic insulin therapy.
One of these drugs created by Aventis - insulin glargine (Lantus), which differs from the human in three amino acid residues. Glargine Sulin is a stable insulin structure, completely soluble at pH 4.0. The drug does not dissolve in the subcutaneous tissue, which has a pH of 7.4, which leads to the formation of microprecipitates at the injection site and its slow release into the bloodstream. The absorption is slowed down by the addition of a small amount of zinc (30 µg/ml). Slowly absorbed, glargine-insulin does not have a peak effect and provides almost basal insulin concentration during the day.
New promising insulin preparations are being developed - inhaled insulin (creation of an insulin-air mixture for inhalation) oral insulin (spray for the oral cavity); buccal insulin (in the form of drops for the oral cavity).
A new method of insulin therapy is the introduction of insulin using an insulin pump, which provides a more physiological way of administering the drug, the absence of insulin depot in the subcutaneous tissue.
The activity of insulin preparations is determined by the method of biological standardization and is expressed in units. 1 unit corresponds to the activity of 0.04082 mg of crystalline insulin. The dose of insulin for each patient is selected individually in a hospital with constant monitoring of the level of HbA1c in the blood and the sugar content in the blood and urine after the administration of the drug. When calculating the daily dose of insulin, it should be taken into account that 1 IU of insulin promotes the absorption of 4-5 g of sugar excreted in the urine. The patient is transferred to a diet with a limited amount of easily digestible carbohydrates.
Simple insulins are administered 30-45 minutes before meals. Intermediate-acting insulins are usually taken twice (half an hour before breakfast and at 18.00 before dinner). Long-acting drugs are administered together with simple insulins in the morning.
Two main variants of insulin therapy are used: traditional and intensive.
Traditional insulin therapy- this is the appointment of standard mixtures of short-acting insulin and NPH-insulin 2/3 of the dose before breakfast, 1/3 before dinner. However, with this type of therapy, hyperinsulinemia occurs, which requires 5-6 meals during the day, hypoglycemia may develop, and a high frequency of late complications of diabetes.
Intensive (basic-bolus) insulin therapy- this is the use of twice a day insulin of medium duration of action (to create a basal level of the hormone) and the additional administration of short-acting insulin before breakfast, lunch and dinner (imitation of bolus physiological secretion of insulin in response to eating). With this type of therapy, the patient himself selects the dose of insulin based on measuring the level of glycemia using a glucometer.
Indications: insulin therapy is absolutely indicated in patients with type 1 diabetes. It should be started in those patients in whom diet, normalization of body weight, physical activity and oral antidiabetic drugs do not provide the desired effect. Simple insulin is used for diabetic coma, as well as for diabetes of any type, if it is accompanied by complications: ketoacidosis, infection, gangrene, heart disease, liver, surgery, postoperative period; to improve the nutrition of patients exhausted by a long illness; as part of a polarizing mixture for heart diseases.
Contraindications: diseases with hypoglycemia, hepatitis, liver cirrhosis, pancreatitis, glomerulonephritis, nephrolithiasis, peptic ulcer of the stomach and duodenum, decompensated heart disease; for long-acting drugs - coma, infectious diseases, during the surgical treatment of patients with diabetes.
Side effect soreness of injections, local inflammatory reactions (infiltrates), allergic reactions, the emergence of resistance to the drug, the development of lipodystrophy.
Insulin overdose can cause hypoglycemia. Symptoms of hypoglycemia: anxiety, general weakness, cold sweat, trembling of the limbs. A significant decrease in blood sugar leads to impaired brain function, the development of coma, seizures and even death. Patients with diabetes should have a few pieces of sugar with them to prevent hypoglycemia. If, after taking sugar, the symptoms of hypoglycemia do not disappear, you need to urgently inject 20-40 ml of a 40% glucose solution intravenously, 0.5 ml of a 0.1% adrenaline solution can be injected subcutaneously. In cases of significant hypoglycemia due to the action of long-acting insulin preparations, patients are more difficult to withdraw from this state than from hypoglycemia caused by short-acting insulin preparations. The presence of a long-acting protamine protein in some preparations explains the frequent cases of allergic reactions. However, injections of long-acting insulin preparations are less painful due to the higher pH of these preparations.
A hormone is a chemical substance that is a biologically active substance produced by the endocrine glands, enters the bloodstream, affects tissues and organs. To date, scientists have been able to decipher the structure of the bulk of hormonal substances, have learned how to synthesize them.
Without pancreatic hormones, the processes of dissimilation and assimilation are impossible; the synthesis of these substances is carried out by the endocrine parts of the organ. In violation of the work of the gland, a person suffers from many unpleasant diseases.
The pancreatic gland is a key organ of the digestive system, it performs endocrine and excretory functions. It produces hormones and enzymes, without which it is not possible to maintain the biochemical balance in the body.
The pancreas consists of two types of tissues, the secretory part, connected to the duodenum, is responsible for the secretion of pancreatic enzymes. The most important enzymes are lipase, amylase, trypsin and chymotrypsin. If deficiency is observed, pancreatic enzyme preparations are prescribed, the use depends on the severity of the violation.
The production of hormones is provided by islet cells, the endocrine part occupies no more than 3% of the total mass of the organ. Islets of Langerhans produce substances that regulate metabolic processes:
- lipid;
- carbohydrate;
- protein.
Endocrine disorders in the pancreas cause the development of a number of dangerous diseases, with hypofunction, diabetes mellitus, glucosuria, polyuria are diagnosed, with hyperfunction, a person suffers from hypoglycemia, obesity of varying severity. Hormone problems also arise if a woman takes contraceptives for a long time.
Pancreatic hormones
Scientists have identified the following hormones secreted by the pancreas: insulin, pancreatic polypeptide, glucagon, gastrin, kallikrein, lipocaine, amylin, vagotinin. All of them are produced by islet cells and are necessary for the regulation of metabolism.
The main hormone of the pancreas is insulin, it is synthesized from the precursor of proinsulin, its structure includes about 51 amino acids.
The normal concentration of substances in the human body over 18 years of age is from 3 to 25 μU / ml of blood. In acute insulin deficiency, diabetes mellitus develops.
Thanks to insulin, the transformation of glucose into glycogen is launched, the biosynthesis of digestive tract hormones is kept under control, and the formation of triglycerides, higher fatty acids, begins.
In addition, insulin reduces the level of harmful cholesterol in the bloodstream, becoming a prophylactic against atherosclerosis of blood vessels. Additionally, transport to cells is improved:
- amino acids;
- macronutrients;
- trace elements.
Insulin promotes protein biosynthesis on ribosomes, inhibits the conversion of sugar from non-carbohydrate substances, lowers the concentration of ketone bodies in human blood and urine, and reduces the permeability of cell membranes to glucose.
The insulin hormone is able to significantly enhance the transformation of carbohydrates into fats with subsequent deposition, is responsible for stimulating ribonucleic (RNA) and deoxyribonucleic (DNA) acids, increases the supply of glycogen accumulated in the liver and muscle tissue. Glucose becomes a key regulator of insulin synthesis, but at the same time the substance does not affect the secretion of the hormone.
The production of pancreatic hormones is controlled by compounds:
- norepinephrine;
- somatostatin;
- adrenalin;
- corticotropin;
- somatotropin;
- glucocorticoids.
Under the condition of early diagnosis of metabolic disorders and diabetes mellitus, adequate therapy can alleviate the condition of a person.
With excessive release of insulin, men are threatened with impotence, patients of either sex have vision problems, asthma, bronchitis, hypertension, premature baldness, the likelihood of myocardial infarction, atherosclerosis, acne and dandruff increases.
If too much insulin is produced, the pancreas itself suffers, it becomes overgrown with fat.
insulin, glucagon
Sugar level
To bring the metabolic processes in the body to normal, it is required to take pancreatic hormone preparations. They should be used strictly as prescribed by the endocrinologist.
Classification of pancreatic hormone preparations: short-acting, medium-term, long-acting. The doctor may prescribe a certain type of insulin or recommend a combination of them.
Short-acting insulin is indicated for diabetes mellitus and excessive sugar in the bloodstream when sweetener tablets do not help. Such funds include Insuman, Rapid, Insuman-Rap, Aktrapid, Homo-Rap-40, Humulin.
The doctor will also offer the patient insulins of medium duration: Mini Lente-MK, Homofan, Semilong-MK, Semilente-MS. There are also long-acting pharmacological agents: Super Lente-MK, Ultralente, Ultratard-NM. Insulin therapy is usually lifelong.
Glucagon
This hormone is included in the list of substances of a polypeptide nature, it contains about 29 different amino acids; in a healthy person, the level of glucagon ranges from 25 to 125 pg / ml of blood. It is considered a physiological insulin antagonist.
Hormonal preparations of the pancreas, containing animal or, stabilize the levels of monosaccharides in the blood. Glucagon:
- secreted by the pancreas;
- has a positive effect on the body as a whole;
- increases the release of catecholamines by the adrenal glands.
Glucagon is able to increase blood circulation in the kidneys, activate metabolism, control the conversion of non-carbohydrate foods into sugar, increase glycemia due to the breakdown of glycogen by the liver.
The substance stimulates gluconeogenesis, in large quantities has an effect on the concentration of electrolytes, has an antispasmodic effect, lowers calcium and phosphorus, and starts the process of fat breakdown.
The biosynthesis of glucagon will require the intervention of insulin, secretin, pancreozymin, gastrin and somatotropin. In order for glucagon to be released, a normal intake of proteins, fats, peptides, carbohydrates and amino acids must be carried out.
Somatostatin, vasointensive peptide, pancreatic polypeptide
Somatostatin
Somatostatin is a unique substance, it is produced by the delta cells of the pancreas and the hypothalamus.
The hormone is necessary for inhibiting the biological synthesis of pancreatic enzymes, lowering the level of glucagon, inhibiting the activity of hormonal compounds and the hormone serotonin.
Without somatostatin, it is impossible to adequately absorb monosaccharides from the small intestine into the bloodstream, reduce the release of gastrin, inhibition of blood flow in the abdominal cavity, and peristalsis of the digestive tract.
Vasointense peptide
This neuropeptide hormone is secreted by cells of various organs: back and brain, small intestine, pancreas. The level of the substance in the bloodstream is quite low, almost does not change even after eating. The main functions of the hormone include:
- activation of blood circulation in the intestine;
- inhibition of the release of hydrochloric acid;
- acceleration of excretion of bile;
- inhibition of water absorption by the intestines.
In addition, there is stimulation of somatostatin, glucagon and insulin, the launch of pepsinogen production in the cells of the stomach. In the presence of an inflammatory process in the pancreas, a violation of the production of neuropeptide hormone begins.
Another substance produced by the gland is a pancreatic polypeptide, but its effect on the body has not yet been fully studied. The physiological concentration in the bloodstream of a healthy person can vary from 60 to 80 pg / ml, excessive production indicates the development of neoplasms in the endocrine part of the organ.
Amylin, lipocaine, kallikrein, vagotonin, gastrin, centroptein
The hormone amylin helps to optimize the amount of monosaccharides, it prevents an increased amount of glucose from entering the bloodstream. The role of the substance is manifested by suppression of appetite (anorexic effect), stopping the production of glucagon, stimulating the formation of somatostatin, and weight loss.
Lipocaine takes part in the activation of phospholipids, oxidation of fatty acids, enhances the effect of lipotropic compounds, and becomes a measure for the prevention of fatty degeneration of the liver.
The hormone kallikrein is produced by the pancreas, but it remains in an inactive state, it begins to work only after entering the duodenum. It lowers the level of glycemia, knocks down pressure. To stimulate the hydrolysis of glycogen in the liver and muscle tissue, the hormone vagotonin is produced.
Gastrin is secreted by gland cells, the gastric mucosa, a hormone-like compound increases acidity, triggers the formation of the proteolytic enzyme pepsin, and normalizes the digestive process. It also activates the production of intestinal peptides, including secretin, somatostatin, cholecystokinin. They are important for the implementation of the intestinal phase of digestion.
Substance centroptein protein nature:
- excites the respiratory center;
- expands the lumen in the bronchi;
- improves the interaction of oxygen with hemoglobin;
- copes well with hypoxia.
For this reason, centroptein deficiency is often associated with pancreatitis and erectile dysfunction in men. Every year more and more new preparations of pancreatic hormones appear on the market, their presentation is carried out, which makes it easier to solve such violations, and they have less and less contraindications.
Pancreatic hormones play a key role in regulating the life of the body, so you need to have an idea about the structure of the organ, take care of your health, and listen to your well-being.
The treatment of pancreatitis is described in the video in this article.
The pancreas functions as an endocrine and endocrine gland. The endocrine function is performed by the insular apparatus. Islets of Langerhans consist of 4 types of cells:
A (a) cells that produce glucagon;
B ((3) cells that produce insulin and amylin;
D (5) cells that produce somatostatin;
F - cells that produce pancreatic polypeptide.
The functions of the pancreatic polypeptide are unclear. Somatostatin, produced in peripheral tissues (as mentioned above), functions as a paracrine secretion inhibitor. Glucagon and insulin are hormones that regulate the level of glucose in the blood plasma in a mutually opposite way (insulin lowers, and glucagon increases). Insufficiency of the endocrine function of the pancreas is manifested by symptoms of insulin deficiency (in connection with which it is considered to be the main hormone of the pancreas).
Insulin is a polypeptide consisting of two chains - A and B, interconnected by two disulfide bridges. The A chain consists of 21 amino acid residues, the B chain consists of 30. Insulin is synthesized in the Golgi apparatus (3-cells in the form of preproinsulin and is converted into proinsulin, which consists of two insulin chains, and a C-protein chain connecting them, consisting of 35 amino acid residues After the C-protein is cleaved and 4 amino acid residues are added, insulin molecules are formed, which are packed into granules and undergo exocytosis. and in total the pancreas contains (including preproinsulin and proinsulin) 8 mg of insulin.Insulin secretion is regulated by neuronal and humoral factors.The parasympathetic nervous system (through M3-cholinergic receptors) enhances, and the sympathetic nervous system (through a2-adrenergic receptors) inhibits the release insulin (3-cells. Somatostatin produced by D-cells depresses, and some tory amino acids (phenylalanine), fatty acids, glucagon, amylin and glucose increase the secretion of insulin. At the same time, the level of glucose in the blood plasma is a determining factor in the regulation of insulin secretion. Glucose enters the (3-cell) and starts a chain of metabolic reactions, as a result of which the concentration of ATP increases in (3-cells. This substance blocks ATP-dependent potassium channels and the membrane (3-cells enters a state of depolarization. As a result of depolarization, the opening frequency increases voltage-gated calcium channels.The concentration of calcium ions in P-cells increases, which leads to increased exocytosis of insulin.
Insulin regulates the metabolism of carbohydrates, fats, proteins, as well as tissue growth. The mechanism of the effect of insulin on tissue growth is the same as that of insulin-like growth factors (see somatotropic hormone). The effect of insulin on metabolism in general can be characterized as anabolic (the synthesis of protein, fats, glycogen is enhanced), while the effect of insulin on carbohydrate metabolism is of primary importance.
It is extremely important to note that those listed in Table. 31.1 changes in tissue metabolism are accompanied by a decrease in the level of glucose in the blood plasma (hypoglycemia). One of the causes of hypoglycemia is an increase in glucose uptake by tissues. The movement of glucose through histohematic barriers is carried out by means of facilitated diffusion (non-volatile transport along an electrochemical gradient through special transport systems). Facilitated glucose diffusion systems are called GLUTs. Specified in table. 31.1 adipocytes and striated muscle fibers contain GLUT 4, through which glucose enters "insulin-dependent" tissues.
Table 31.1. Effect of insulin on metabolism
The influence of insulin on metabolism is carried out with the participation of specific membrane insulin receptors. They consist of two a- and two p-subunits, while the a-subunits are located on the outer side of the membranes of insulin-dependent tissues and have binding centers for insulin molecules, and the p-subunits are a transmembrane domain with tyrosine kinase activity and a tendency to mutual phosphorylation. When the insulin molecule binds to the α-subunits of the receptor, endocytosis occurs, and the insulin-receptor dimer is immersed in the cytoplasm of the cell. As long as the insulin molecule is bound to the receptor, the receptor remains in an activated state and stimulates phosphorylation processes. After separation of the dimer, the receptor returns to the membrane, and the insulin molecule is degraded in lysosomes. Phosphorylation processes triggered by activated insulin receptors lead to the activation of certain enzymes.
carbohydrate metabolism and increased synthesis of GLUT. Schematically, this can be represented as follows (Fig. 31.1):
With insufficient production of endogenous insulin, diabetes mellitus occurs. Its main symptoms are hyperglycemia, glucosuria, polyuria, polydipsia, ketoacidosis, angiopathy, etc.
Insulin deficiency can be absolute (an autoimmune process leading to the death of the islet apparatus) and relative (in the elderly and obese people). In this regard, it is customary to distinguish between type 1 diabetes mellitus (absolute insulin deficiency) and type 2 diabetes mellitus (relative insulin deficiency). In both forms of diabetes, a diet is indicated. The procedure for prescribing pharmacological drugs for different forms of diabetes is not the same.
Antidiabetic agents
Used in type 1 diabetes
- Insulin preparations (replacement therapy)
- Synthetic antidiabetic agents
- insulin preparations insulin preparations
Insulin preparations can be produced from the pancreas of slaughtered cattle - these are bovine (beef) and porcine insulin. In addition, there is a genetically engineered way to obtain human insulin. Insulin preparations obtained from the pancreas of slaughter animals may contain impurities of proinsulin, C-protein, glucagon, somatostatin. Modern technologies for
allow to obtain highly purified (monocomponent), crystallized and monopeak (chromatographically purified with the release of the "peak" of insulin) preparations.
The activity of insulin preparations is determined biologically and is expressed in units of action. Insulin is used only parenterally (subcutaneously, intramuscularly and intravenously), since, being a peptide, it is destroyed in the gastrointestinal tract. Being subjected to proteolysis in the systemic circulation, insulin has a short duration of action, which is why long-acting insulin preparations have been created. They are obtained by precipitation of insulin with protamine (sometimes in the presence of Zn ions to stabilize the spatial structure of insulin molecules). The result is either an amorphous solid or relatively slightly soluble crystals. When injected under the skin, such forms provide a depot effect, slowly releasing insulin into the systemic circulation. From a physicochemical point of view, prolonged forms of insulin are suspensions, which serves as an obstacle to their intravenous administration. One of the disadvantages of long-acting forms of insulin is a long latent period, so sometimes they are combined with non-long-acting insulin preparations. This combination ensures the rapid development of the effect and its sufficient duration.
Insulin preparations are classified according to the duration of action (main parameter):
- Rapid-acting insulin (onset of action usually after 30 minutes; maximum action after 1.5-2 hours, total duration of action 4-6 hours).
- Long-acting insulin (onset after 4-8 hours, peak after 8-18 hours, total duration 20-30 hours).
- Intermediate-acting insulin (onset after 1.5-2 hours, peak after
- 12 hours, total duration 8-12 hours).
- Intermediate-acting insulin in combinations.
Side effects. At present, either genetically engineered human insulins or highly purified porcine insulins are used in medical practice. In this regard, complications of insulin therapy are relatively rare. Allergic reactions, lipodystrophy at the injection site are possible. Excessive hypoglycemia may develop if insulin doses are too high or if dietary carbohydrates are insufficient. Its extreme option is a hypoglycemic coma with loss of consciousness, convulsions and symptoms of cardiovascular insufficiency. With a hypoglycemic coma, the patient should be injected intravenously with a 40% glucose solution in an amount of 20-40 (but not more than 100) ml.
Since insulin preparations are used for life, it should be borne in mind that their hypoglycemic effect may be altered by other drugs. Enhance the hypoglycemic effect of insulin: a-blockers, P-blockers, tetracyclines, salicylates, disopyramide, anabolic steroids, sulfonamides. Weaken the hypoglycemic effect of insulin: p-agonists, sympathomimetics, glucocorticosteroids, thiazide diuretics.
Contraindications: diseases occurring with hypoglycemia, acute diseases of the liver and pancreas, decompensated heart defects.
Preparations of genetically engineered human insulin
Actrapid NM is a solution of biosynthetic human insulin of short and fast action in 10 ml vials (1 ml of the solution contains 40 or 100 IU of insulin). It can be produced in cartridges (Actrapid NM Penfill) for use in the Novo-Pen insulin pen. Each cartridge contains 1.5 or 3 ml of solution. The hypoglycemic effect develops after 30 minutes, reaches a maximum after 1-3 hours and lasts 8 hours.
Isophane-insulin NM is a neutral suspension of genetically engineered insulin with an average duration of action. Vials of 10 ml of suspension (40 IU in 1 ml). Hypoglycemic action begins after 1-2 hours, reaches a maximum after 6-12 hours, lasts 18-24 hours.
Monotard HM is a composite suspension of human zinc insulin (contains 30% amorphous and 70% crystalline zinc insulin. 10 ml vials of suspension (40 or 100 IU per 1 ml). Hypoglycemic effect begins after
- h, reaches a maximum after 7-15 hours, lasts 24 hours.
Pig insulin preparations
Insulin neutral for injections (InsulinS, AktrapidMS) - a neutral solution of monopeak or monocomponent porcine insulin of short and fast action. Vials of 5 and 10 ml (1 ml of solution contains 40 or 100 IU of insulin). The hypoglycemic effect begins 20-30 minutes after subcutaneous administration, reaches a maximum after 1-3 hours and lasts 6-8 hours. For systematic treatment, it is administered under the skin, 15 minutes before meals, the initial dose is from 8 to 24 IU (ED) , the highest single dose - 40 IU. For the relief of diabetic coma, it is administered intravenously.
Insulin isophane is a monopeak monocomponent porcine isophane protamine insulin. The hypoglycemic effect begins after 1-3 hours, reaches a maximum after 3-18 hours, lasts about 24 hours. It is most often used as a component of combined preparations with short-acting insulin.
Insulin Lente SPP is a neutral compound suspension of monopeak or monocomponent porcine insulin (contains 30% amorphous and 70% crystalline zinc insulin). Vials of 10 ml of suspension (40 IU in 1 ml). The hypoglycemic effect begins 1-3 hours after subcutaneous administration, reaches a maximum after 7-15 hours, and lasts 24 hours.
Monotard MS is a neutral compound suspension of monopeak or monocomponent porcine insulin (contains 30% amorphous and 70% crystalline zinc insulin). Vials of 10 ml suspension (40 or 100 IU in 1 ml). The hypoglycemic effect begins after 2.5 hours, reaches a maximum after 7-15 hours, and lasts 24 hours.
