Pancreatic hormone preparations. Biological role of pancreatic hormones
The main hormones of the pancreas:
· insulin (normal blood concentration in a healthy person is 3-25 µU/ml, in children 3-20 µU/ml, in pregnant and elderly people 6-27 µU/ml);
glucagon (plasma concentration 27-120 pg/ml);
c-peptide (normal level 0.5-3.0 ng/ml);
· pancreatic polypeptide (fasting serum PP level 80 pg/ml);
gastrin (normal range 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 occurs due to 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 production in the liver. In addition, glucagon promotes the breakdown of lipids in adipose tissue.
A growth hormone somatotropin increases alpha cell activity. In contrast, the delta cell hormone somatostatin inhibits the formation and secretion of glucagon, since it blocks the entry of Ca ions into alpha cells, 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 activity.
Functions centropnein– stimulation of the respiratory center, promoting relaxation of bronchial smooth muscles, 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, constituting 1% of its mass. The islets are composed of alpha, beta and delta cells that produce glucagon, insulin and somatostatin (inhibiting the secretion of growth hormone), respectively.
Insulin Normally, it is the main regulator of blood glucose levels. Even a slight increase in blood glucose causes insulin secretion and stimulates its further synthesis by beta cells.
The mechanism of action of insulin is due to the fact that hubbub enhances the absorption of glucose by tissues and promotes its conversion into glycogen. Insulin, by increasing the permeability of cell membranes to glucose and reducing 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, striated muscle cells are also glycogen depots.
CLASSIFICATION OF INSULIN PREPARATIONS
All insulin preparations produced by global pharmaceutical companies differ mainly in three main characteristics:
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 the 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, insulinrap SPP, monotard MS, semilente, etc.);
b) synthetic or, more precisely, species-specific, human insulins. These drugs are obtained using genetic engineering methods using DNA-recombinant technology, and therefore they are most often called DNA-recombinant insulin preparations (actrapid NM, homophane, isophane NM, humulin, ultratard NM, monotard NM, etc.).
III. Based on the speed of onset of effects and their duration, they are distinguished:
a) fast-acting, 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, total duration of effect - 12-16 hours); - semilente MS; - humulin N, humulin lente, homophane; - tape, tape MS, monotard MS (2-4 hours and 20-24 hours, respectively); - iletin I NPH, iletin II NPH; - insulong SPP, insulin lente GPP, SPP, etc.
c) medium-duration drugs 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 com. 15/85; 25/75; 50/50 (valid for 10-16 hours).
d) long-acting drugs:
Ultralente, ultralente MS, ultralente NM (up to 28 hours);
Insulin superlente SPP (up to 28 hours);
Humulin ultralente, ultratard NM (up to 24-28 hours).
ACTRAPID, obtained from the beta cells of porcine pancreatic islets, is produced as an official drug in 10 ml bottles, most often with an activity of 40 units per 1 ml. It is administered parenterally, most often under the skin. This drug has a rapid sugar-lowering effect. The effect develops after 15-20 minutes, and the peak of action is observed after 2-4 hours. The total duration of the hypoglycemic effect is 6-8 hours in adults, and up to 8-10 hours in children.
Advantages of rapid short-acting insulin preparations (actrapide):
1) act quickly;
2) give a physiological peak concentration in the blood;
3) act for a short time.
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. For the most severe forms of non-insulin-dependent diabetes mellitus in adults.
3. For diabetic (hyperglycemic) coma. In this case, the drugs are administered both under the skin and into a vein.
ANTIDIABETIC (HYPOGLYCEMIC) ORAL DRUGS
Stimulating endogenous insulin secretion (sulfonylureas):
1. First generation drugs:
a) chlorpropamide (syn.: diabinez, catanil, 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.: glyurenorm);
d) gliclazide (syn.: Predian, Diabeton).
II. Affecting the metabolism and absorption of glucose (biguanides):
a) buformin (glybutide, adebit, sibin retard, dimethyl biguanide);
b) metformin (gliformin). III. Slowing glucose absorption:
a) glucobay (acarbose);
b) guar (guar gum).
BUTAMID (Butamidum; issued in tablets of 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 beta cells of the pancreas and their increased secretion of insulin. The onset of action is 30 minutes, its duration is 12 hours. The drug is prescribed 1-2 times a day. Butamide is excreted by the kidneys. This drug is well tolerated.
Side effects:
1. Dyspepsia. 2. Allergies. 3. Leukocytopenia, thrombocytopenia. 4. Hepatotoxicity. 5. Tolerance may develop.
BIGUANIDES are derivatives of guanidine. The two most famous drugs are:
Buformin (glybutide, adebit);
Metformin.
GLIBUTID (Glibutidum; issue in tablets 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 excess weight).
They are most often used in patients with diabetes mellitus-II, accompanied by obesity.
The pancreas produces several hormones:
glucagon, insulin, somatostatin, gastrin.
Of them insulin has the greatest practical significance.
Insulin is produced V- cells of the islets of Langerhans.
Pancreatic cells continually release small basal amounts of insulin.
In response to various stimuli (especially glucose), insulin production increases significantly.
Lack of insulin or excess of factors that counteract its activity,
lead to development diabetes mellitus - serious illness,
which is characterized by:
high blood glucose levels (hyperglycemia)
excreting it in the urine (concentrations in primary urine exceed the possibilities
subsequent reabsorption - glucosuria)
accumulation of products of impaired fat metabolism - acetone, hydroxybutyric acid -
in the blood with intoxication and development of acidosis (ketoacidosis)
excreting them in the urine (ketonuria)
progressive damage to the renal capillaries
and retina (retinopathy)
nerve tissue
generalized atherosclerosis
Mechanism of action of insulin:
1, Receptor binding
There are special receptors in cell membranes for insulin,
interacting with which the hormone increases their absorption of glucose several times.
Important for tissues that receive very little glucose without insulin (muscle, fat).
The supply of glucose also increases to organs that are sufficiently supplied with it without insulin (liver, brain, kidneys).
2. Entry of glucose transport protein into the membrane
As a result of the binding of the hormone to the receptor, the enzymatic part of the receptor (tyrosine kinase) is activated.
Tyrosine kinase involves the work of other metabolic enzymes in the cell and the release of glucose transport 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 in the cell are enhanced and catabolic processes 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 into glucose)
Accelerate glycogen formation
(activates glucokinase and glycogen synthetase) and
inhibits glycogenolysis (inhibits phosphorylase)
Fat metabolism
Inhibits lipolysis (inhibits 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:
To the liver
- increased glucose deposition in the form of glycogen due to
inhibition of glycogenolysis,
ketogenesis,
gluconeogenesis
(this is partly ensured by increased transport of glucose into cells and its phosphorylation)
For skeletal muscles
- activation of protein synthesis due to
enhancing amino acid transport and increasing ribosomal activity,
- activation of glycogen synthesis,
spent during muscular work
(due to increased glucose transport).
To adipose tissue
Increased triglyceride deposition
(the most effective 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 n 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 Endocrinopathies Diabetes induced by drugs, chemicals (alloxan, nitrophenylurea (rat poison), hydrogen cyanide, etc.) Infections Uncommon forms of insulin-mediated diabetes Other genetic syndromes sometimes associated with diabetes |
| Gestational diabetes | Diabetes only during pregnancy |
The result of using insulin - multilateral positive changes in exchange:
Activation of carbohydrate metabolism.
Enhanced glucose transport into cells
Increased use of glucose in the tricarboxylic acid cycle and glycerophosphate supply Increased conversion of glucose to glycogen
Inhibition of gluconeogenesis
Reducing blood sugar levels - stopping glucosuria.
Transformation of fat metabolism towards lipogenesis.
Activation of triglyceride formation from free fatty acids
as a result of the entry of glucose into adipose tissue and the formation of glycerophosphate
Decreased levels of free fatty acids in the blood and
reducing their conversion in the liver into ketone bodies - eliminating 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 amino acid reserves by inhibiting 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 McLeod)
In 1958 - for establishing the chemical composition (Frederick Sanger)
The incredible speed of introducing the discovery into practice:
From the brilliant insight to testing the effect of the drug on dogs with a removed pancreas, only 3 months passed.
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.
WordBantingbecame generally known in English 60 years before the discovery of insulin - thanks to William Banting, an undertaker and an enormous fat man.
His house, sign and staircase still remain on St James's Street in London.
One day Bunting was unable to go down these stairs because he had become so fat.
Then he went on a starvation diet.
Banting outlined his experience of losing weight in the brochure “A Letter to the Public on Obesity.” The book was published in 1863 and instantly became a bestseller.
His system became so popular that the word “banting” in English took on 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 - Hunger diet and Best.
Until the beginning of the twentieth century diabetes-induced weakness, fatigue, constant thirst, diabetes (up to 20 liters of urine per day), non-healing ulcers at the site of the slightest wound, etc. could be prolonged in the only empirically found way - by starving.
For type 2 diabetes, this helped for quite a long time, for type 1 – for several years.
Cause of diabetes became partly clear in 1674,
when London doctor Thomas Willis tasted a patient's urine.
It turned out to be sweet due to the fact that the body got rid of sugar by any means.
Association of diabetes with pancreatic dysfunction discovered in the middle of the nineteenth century.
Leonid Vasilievich Sobolev
In 1900-1901 he formulated the principles of producing insulin.
Blood sugar levels are regulated by the hormone of the islets of Langerhans of the pancreas. –
suggested in 1916 by the English physiologist Charpy-Schaefer.
The main thing remained - isolate insulin from the pancreas of animals and use it to treat humans.
The first person to succeed was a Canadian doctor. Fred Bunting .
Banting took up the problem of diabetes without work experience or serious scientific training.
Straight from his parents' farm, he entered the University of Toronto.
Then he served in the army, worked as a surgeon in a field hospital, and was seriously wounded.
After demobilization, Banting took a position as a junior lecturer in anatomy and physiology at the University of Toronto.
He immediately suggested to the head of the department, professor John McLeod release pancreatic hormones.
McLeod, a leading expert in the field of diabetes, knew very well how many famous scientists had been struggling with this problem for decades without success, so he declined the offer.
But a few months later, Banting came up with an idea that struck him at 2 a.m. in April 1921:
ligate the pancreatic ducts so that it stops producing trypsin.
The idea turned out to be correct, because... trypsin stopped breaking down insulin protein molecules, and insulin became possible to isolate.
McLeod went to Scotland and allowed Banting to use his laboratory for 2 months and conduct experiments at his own expense. He even assigned a student as an assistant Charles Best.
Best was able 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 obtain 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 had managed to achieve, he immediately involved the entire department, led by himself, in the work.
Banting did not apply for a patent.
The developers first tried the drug on themselves - according to the custom of doctors of that time.
The rules were simple back then, and diabetics were dying, so improvements in isolation and purification methods were carried out in parallel with clinical applications.
They took the risk of injecting a boy who was expected to die in a few days.
The attempt was unsuccessful - the crude pancreas extract had no effect
But after 3 weeks January 23, 1922 After injecting poorly purified insulin, 14-year-old Leonard Thompson's blood sugar levels dropped.
Among Banting's first patients was his friend, also a doctor.
Another patient, a teenage girl, was brought from the USA to Canada by her mother, a doctor.
The girl was given an injection right at the station, she was already in a coma.
After she came to her senses, the girl, receiving insulin, lived for another 60 years.
The industrial production of insulin was started by a doctor whose wife, an endocrinologist, suffered from diabetes, the Dane Augus Krogh ( Novo Nordisk- a Danish company that is still one of the largest insulin manufacturers).
Banting shared his prizes equally with Best, and McLeod with Collip (biochemist).
In Canada, Banting 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 as 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 research Banting and Best Institute, was elected member Royal Society in London, received British knighthood.
With the outbreak of World War 2, he went to the front as a volunteer and organizer of medical care.
On February 22, 1941, Bunting died when the plane he was flying in crashed over the snowy desert of Newfoundland.
Banting Monuments stand in Canada at his homeland and at the place of his death.
November 14 - Banting's birthday - celebrated as diabetes day .
Insulin preparations
U ultra-short-acting
Lizpro (Humalog)
Onset of action in 15 minutes, duration 4 hours, taken before meals.
Regular crystalline insulin (outdated)
actrapid MK, MP (pork), actrapid H , ilitin R (regular), humulin R
Onset of action in 30 minutes, duration 6 hours, taken 30 minutes before meals.
Intermediate action
Semilente MK
Onset of action after 1 hour, duration 10 hours, taken one hour before meals.
Lente, Lente MK
Onset of action after 2 hours, duration 24 hours, taken 2 hours before meals.
Homophane, protophane H , monotard H , MK
Onset of action in 45 minutes, duration 20 hours, taken 45 minutes before meals.
Long-acting
Ultralente MK
Onset of action after 2 hours, duration 30 hours, taken 1.5 hours before meals.
Ultralente iletin
Onset of action after 8 hours, duration 25 hours, taken 2 hours before meals.
Ultratard H
Humulin U
Onset of action after 3 hours, duration 25 hours, taken 3 hours before meals.
Short-acting drugs:
Administered by injection - subcutaneously or (for hyperglycemic coma) intravenously
Disadvantages - high activity at the peak of action (which creates the risk of hypoglycemic coma), short duration of action.
Medium duration drugs:
Used in the treatment of compensated diabetes, after treatment with short-acting drugs with determination of insulin sensitivity.
Long-acting drugs:
They are administered only subcutaneously.
It is advisable to combine drugs with short and medium duration of action.
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.
Porcine insulin differs from humans by only one amino acid.
Human insulin obtained using recombinant DNA technology (by placing DNA in a yeast cell and hydrolyzing the produced proinsulin into an insulin molecule).
Insulin delivery systems :
Infusion systems.
Portable pumps.
Implantable auto-injector
A titanium reservoir with a supply of insulin for 21 days is implanted.
It is surrounded by a reservoir filled with photorucarbon gas.
A titanium reservoir catheter is connected to a blood vessel.
When exposed to heat, the gas expands and provides a continuous supply of insulin into the blood.
Nasal spray
In the fall of 2005, the US Food and Drug Administration approved the first insulin drug in the form of a nasal spray.
Regular insulin injections
Insulin dosing : strictly individual.
The optimal dose should reduce blood glucose levels to normal, eliminate glucosuria and other symptoms of diabetes.
Subcutaneous injection areas (different absorption rates): anterior surface of the abdominal wall, outer surface of the shoulders, anterior outer surface of the thighs, buttocks.
Short-acting drugs– in the abdominal area (faster absorption),
Extended-release drugs– in the thighs or buttocks.
The shoulders are uncomfortable for self-injections.
The effectiveness of therapy is monitored by
Systematic determination of “hungry” blood sugar levels and
Its excretion in urine per day
The most rational treatment option for type 1 diabetes is
A regimen of multiple insulin injections that simulates physiological insulin secretion.
Under physiological conditions
basal (background) insulin secretion occurs continuously and amounts to 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 insulin secretion can be simulated as follows:
Short-acting medications are administered before each meal.
Basal secretion is supported by long-acting drugs.
Complications of insulin therapy:
Hypoglycemia
As a result
Untimely eating,
Unusual physical activity
Injecting an unreasonably high dose of insulin.
Manifests
dizzy
Tremors,
Weakness
Hypoglycemic coma
Possible development of insulin shock, loss of consciousness, and death.
Docked taking glucose.
Complications of diabetes
Diabetic coma
Due to
Using insufficient doses of insulin
Diet disorders
Stressful situations.
Without immediate intensive care, diabetic coma (accompanied by cerebral edema)
always leads to death.
As a result
Increasing intoxication of the central nervous system 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 muscles),
Blood potassium concentration falls sharply. The result is cardiac dysfunction.
Immune disorders.
Insulin allergy, immune resistance to insulin.
Lipodystrophy at the injection site.
Parathyroidin- the drug parathyroid hormone parathyrin (parathyroid hormone), has recently been used very rarely, since there are more effective means. 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 the regulation of calcium and phosphorus metabolism. 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 associated not with the direct influence of parathyrin, but with an increase in formation under its influence calcitriol (the active form of calciferol in the kidneys). In the renal tubules, parathyrine increases calcium reabsorption and decreases phosphate reabsorption. At the same time, the phosphorus content in the blood decreases, while the calcium level 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 bone deformation and fractures. In cases of hyperproduction of parathyrin, administer calcitonin, which prevents the leaching of calcium from bone tissue.
Indications: hypoparathyroidism, to prevent tetany due to hypocalcemia (in acute cases, calcium supplements or their combination with parathyroid hormone preparations should be administered intravenously).
Contraindications: increased calcium content in the blood, with heart disease, kidney disease, allergic diathesis.
Dihydrotachysterol (tahistin) - its chemical structure is close to ergocalciferol (vitamin D2). Increases the absorption of calcium in the intestines, while simultaneously increasing the excretion of phosphorus in the urine. Unlike ergocalciferol, there is no vitamin D activity.
Indications: disorders of phosphorus-calcium metabolism, including hypocalcic convulsions, spasmophilia, allergic reactions, hypoparathyroidism.
Contraindications: increased calcium levels in the blood.
Side effect: nausea.
Pancreatic hormonal drugs.
insulin preparations
Pancreatic hormones are of great importance in regulating metabolic processes in the body. IN β cells pancreatic islets are synthesized insulin, which has a pronounced hypoglycemic effect, in a-cells contrainsular hormone is produced glucagon, which has a hyperglycemic effect. Besides, δ-clititis pancreas produces somatostatin .
When insulin secretion is insufficient, diabetes mellitus (DM) develops - diabetes mellitus - a disease that occupies one of the dramatic pages of world medicine. According to WHO estimates, the number of people with diabetes worldwide in 2000 was 151 million people; by 2010, it is expected to increase to 221 million people, and by 2025 - 330 million people, which suggests that it is a global epidemic. Diabetes causes the earliest disability of all diseases, high mortality, frequent blindness, renal failure, and is also a risk factor for cardiovascular diseases. Diabetes ranks first among endocrine diseases. The United Nations has declared diabetes to be a pandemic of the 21st century.
According to the WHO classification (1999.) There are two main types of the disease - diabetes type 1 and type 2(according to insulin-dependent and non-insulin-dependent diabetes). Moreover, the increase in the number of patients is predicted mainly due to patients with type 2 diabetes, who currently make up 85-90% of the total number of patients with diabetes. This type of diabetes is diagnosed 10 times more often than type 1 diabetes.
For the treatment of diabetes, diet, insulin preparations and oral antidiabetic drugs are used. Effective treatment of patients with CD should ensure approximately the same basal insulin levels throughout the day and prevent hyperglycemia that occurs after eating (postprandial glycemia).
The main and only objective indicator of the effectiveness of diabetes therapy, reflecting the state of disease compensation, is the level of glycosylated hemoglobin (HbA1C or A1C). HbA1c or A1C is hemoglobin, which is covalently bound to glucose and is an indicator of the level of glycemia over the previous 2-3 months. Its level correlates well with blood glucose levels and the likelihood of diabetes complications. A 1% decrease in the level of glycosylated hemoglobin is accompanied by a 35% decrease in the risk of developing diabetes complications (regardless of the initial HbA1c level).
The basis of treatment for CD is properly selected hypoglycemic therapy.
Historical reference. The principles of producing insulin were developed by L.V. Sobolev (in 1901), who in an experiment on the glands of newborn calves (they do not yet contain trypsin, insulin breaks down) showed that the substrate of the internal secretion of the pancreas is the pancreatic islets (Langerhans). In 1921, Canadian scientists F. G. Banting and C. H. Best isolated pure insulin and developed a method for industrial production. 33 years later, Sanger and his colleagues deciphered the primary structure of cattle insulin, for which they received the Nobel Prize.
The creation of insulin preparations occurred in several stages:
First generation insulins - pork and cow (bovine) insulin;
Second generation insulins - monopeak and monocomponent insulins (50s of the XX century)
Third generation insulins - semi-synthetic and genetically engineered insulin (80s of the 20th century)
Preparation of insulin analogues and inhaled insulin (late 20th - early 21st centuries).
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). When treated with bovine insulin, adverse immunological reactions occurred more often than when treated 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 and insulins obtained by gel chromatography. It was later found that they contain small amounts of insulin-like peptides. The next step was the creation of monocomponent insulins (MK-insulins), which were obtained through additional purification using ion exchange chromatography. When using monocomponent porcine insulins, the production of antibodies and the development of local reactions in patients were rare (currently bovine and monopik and porcine insulins are not used in Ukraine).
Human insulin preparations are obtained either by a semi-synthetic method using an enzymatic-chemical replacement at position B30 in pork insulin of the amino acid alanine with 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 to improve and search for new forms of insulin.
According to its chemical structure, insulin is a protein, the molecule of which consists of 51 amino acids, forming two polypeptide chains connected by two disulfide bridges. Concentration plays a dominant role in the physiological regulation of insulin synthesis. 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 promotes the entry 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 influenced by amino acids, free fatty acids, glucagon, secretin, electrolytes (especially Ca 2+), and 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, and minerals. The main thing in the action of insulin is its regulating effect on carbohydrate metabolism and reducing blood glucose levels. This is achieved by the fact that insulin promotes the active transport of glucose and other hexoses, as well as pentoses across cell membranes and their utilization by the liver, muscle and fat tissues. Insulin stimulates glycolysis, induces the synthesis of the enzymes glucokinase, phosphofructokinase and pyruvate kinase, stimulates the pentose phosphate cycle, activating glucose-6-phosphate dehydrogenase, increases glycogen synthesis, activating glycogen synthetase, the activity of which is reduced in patients with diabetes. On the other hand, the hormone suppresses glycogenolysis (decomposition of glycogen) and gluconeogenesis.
Insulin plays an important role in stimulating the biosynthesis of nucleotides, 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, and 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 the construction of cell membranes.
With insufficient amounts of insulin, lipogenesis is suppressed, lipid production 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, which are essential in the development of atherosclerosis, increases. Insulin prevents the body from losing fluid and K+ in the urine.
The essence of the molecular mechanism of insulin action on intracellular processes is not fully disclosed. However, the first link 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). In this case, the kinase activity of the β-subunit of the receptor (Tyrosine kinase) is stimulated and it autophosphorylates. An “insulin + receptor” complex is created, which penetrates into the cell through endocytosis, where insulin is released and the cellular mechanisms of the hormone’s action are triggered.
Not only secondary messengers take part in the cellular mechanisms of insulin action: cAMP, Ca 2+, calcium-calmodulin complex, inositol triphosphate, diacylglycerol, but also fructose 2,6-biphosphate, which is called the third mediator of insulin in its effect on intracellular biochemical processes. It is the increase in the level of fructose-2,6-biphosphate under the influence of insulin that promotes the utilization of glucose from the blood and 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, and Golgi complex. Administration of insulin to patients with diabetes helps reduce blood glucose levels and the accumulation of glycogen in tissues, reducing glucosuria and associated polyuria and 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. Losing weight stops and excessive hunger disappears ( bulimia ). The detoxification function of the liver increases, and 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 administration 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 medicinal properties have led to modifications in the formula of human insulin and to the development of short-acting insulin analogues.
The first analogue is lisproinsulin (humalogist) is identical to human insulin except for the position of lysine and proline at positions 28 and 29 of the B chain. This change did not affect the activity of the A-chain, but reduced the processes of self-association of insulin molecules and ensured accelerated absorption from the subcutaneous depot. After injection, the onset of action is 5-15 minutes, the peak is reached in 30-90 minutes, the duration of action is 3-4 hours.
The second analogue is aspart(tradename - novo-rapid) modified by replacing one amino acid at 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 is glulisine(tradename epaidra) is practically similar to endogenous human insulin and biosynthetic regular human insulin with certain structural changes in the formula. Thus, in the V3-position, asparagine is replaced by lysine, and 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, glulisine (epaidra) improves glycemic control, also inhibits lipolysis and proteolysis, accelerates protein synthesis, activates insulin receptors and its substrates, fully consistent with the effect of regular human insulin on these elements.
2. Long-acting insulin preparations:
2.1. Medium duration (onset of action after subcutaneous administration after 1.5-2 hours, duration 8-12 hours). These drugs are also called insulin semilente. This group includes insulins based on neutral Protamine Hagedorn: B-insulin, Monodar B, Farmasulin HNP. Since HNP-insulin contains insulin and protamine in equal, isophane-based ratios, they are also called isophane-type insulins;
2.2. Long-lasting (ultralente) with onset of action after 6-8 hours, duration of action 20-30 hours. This includes insulin preparations containing Zn2 +: suspension-insulin-ultralente, Farmasulin HL. Long-acting drugs are administered only subcutaneously or intramuscularly.
3. Combined preparations containing standard mixtures of drugs of group 1 with NPH insulins in different ratios of groups 1 and 2: 30/70, 20/80, 10/90, etc. - Monodar K ZO, Farmasulin 30/70 t. Some drugs are produced in special syringe tubes.
To achieve maximum glycemic control in patients with diabetes, an insulin therapy regimen is needed that completely simulates the physiological profile of insulin throughout the day. Long-acting insulins have their drawbacks, in particular the presence of a peak effect 5-7 hours after administration of the drug leads to the development of hypoglycemia, especially at night. These shortcomings have led to the development of insulin analogues with the pharmacokinetic properties of effective basal insulin therapy.
One of these drugs created by Aventis is insulin glargine (Lantus), which differs from human by three amino acid residues. Glargine-in Sulin is a stable insulin structure, completely soluble at pH 4.0. The drug does not dissolve in 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 addition of a small amount of zinc (30 mcg/ml) helps slow down absorption. Being slowly absorbed, insulin glargine does not have a peak effect and provides almost basal insulin concentrations throughout the day.
New promising insulin preparations are being developed - inhaled insulin (creation of an insulin-air mixture for inhalation) oral insulin (oral spray); buccal insulin (in the form of oral drops).
A new method of insulin therapy is the administration of insulin using an insulin pump, which provides a more physiological method of administering the drug, the absence of an 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 setting with constant monitoring of HbA1c levels in the blood and sugar levels in the blood and urine after the drug is prescribed. When calculating the daily dose of insulin, it should be taken into account that 1 unit of insulin promotes the absorption of 4-5 g of sugar excreted in the urine. The patient is put on a diet with a limited amount of easily digestible carbohydrates.
Simple insulins are administered 30-45 minutes before meals. Intermediate-acting insulins are usually used twice (half an hour before breakfast and at 18.00 before dinner). Long-acting drugs are administered together with simple insulins in the morning.
There are two main types of insulin therapy: traditional and intensive.
Traditional insulin therapy- this is the administration of standard mixtures of short-acting insulin and NPH-insulin 2/3 doses before breakfast, 1/3 before dinner. However, with this type of therapy, hyperinsulinemia occurs, which requires 5-6 times the consumption of food during the day, the development of hypoglycemia is possible, and a high incidence of late complications of diabetes.
Intensive (basal-bolus) insulin therapy- this is the use of intermediate-acting insulin twice a day (to create a basal level of the hormone) and the additional administration of short-acting insulin before breakfast, lunch and dinner (simulating bolus physiological secretion of insulin in response to food intake). With this type of therapy, the patient himself selects the dose of insulin based on measuring the glycemic level using a glucometer.
Indications: Insulin therapy is absolutely indicated for 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 necessary 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 disease, surgical operations, postoperative period; to improve the nutrition of patients exhausted by a long-term illness; as part of a polarizing mixture for heart diseases.
Contraindications: diseases with hypoglycemia, hepatitis, liver cirrhosis, pancreatitis, glomerulonephritis, kidney stones, gastric and duodenal ulcers, decompensated heart defects; for long-acting drugs - coma, infectious diseases, during surgical treatment of patients with diabetes.
Side effect painful injections, local inflammatory reactions (infiltrates), allergic reactions, the emergence of drug resistance, the development of lipodystrophy.
An overdose of insulin may cause hypoglycemia. Symptoms of hypoglycemia: anxiety, general weakness, cold sweat, trembling limbs. A significant decrease in blood sugar leads to impaired brain function, coma, seizures and even death. Patients with diabetes should have several 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, it is more difficult to recover patients from this condition than from hypoglycemia caused by short-acting insulin preparations. The presence of protamine protein in some long-acting drugs explains the frequent cases of allergic reactions. However, injections of long-acting insulin preparations are less painful, which is associated with the higher pH of these drugs.
A hormone is a chemical substance that is a biologically active substance, produced by the endocrine glands, enters the bloodstream, and has an effect on tissues and organs. Today, scientists have been able to decipher the structure of the bulk of hormonal substances and have learned 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. If the functioning of the gland is disrupted, a person suffers from many unpleasant diseases.
The pancreatic gland is a key organ of the digestive system; it performs incretory and excretory functions. It produces hormones and enzymes, without which it is impossible to maintain biochemical balance in the body.
The pancreas consists of two types of tissue; 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 disorder.
The production of hormones is ensured by islet cells; the endocrine part occupies no more than 3% of the total mass of the organ. The 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, and polyuria are diagnosed; with hyperfunction, a person suffers from hypoglycemia and obesity of varying severity. Problems with hormones also occur if a woman takes birth control 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 pancreatic hormone is insulin; it is synthesized from the precursor proinsulin; its structure includes about 51 amino acids.
The normal concentration of substances in the body of a person over 18 years of age is from 3 to 25 µU/ml of blood. With acute insulin deficiency, diabetes mellitus develops.
Thanks to insulin, the transformation of glucose into glycogen is triggered, the biosynthesis of digestive tract hormones is kept under control, and the formation of triglycerides and higher fatty acids begins.
In addition, insulin reduces the level of harmful cholesterol in the bloodstream, becoming a preventative against vascular atherosclerosis. Additionally, transport to cells is improved:
- amino acids;
- macroelements;
- microelements.
Insulin promotes protein biosynthesis on ribosomes, inhibits the process of converting 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 capable of significantly increasing the transformation of carbohydrates into fats with subsequent deposition, is responsible for the stimulation of ribonucleic (RNA) and deoxyribonucleic (DNA) acids, increases the supply of glycogen accumulated in the liver and muscle tissue. The key regulator of insulin synthesis becomes glucose, but at the same time the substance does not affect hormone secretion in any way.
The production of pancreatic hormones is controlled by compounds:
- norepinephrine;
- somatostatin;
- adrenalin;
- corticotropin;
- somatotropin;
- glucocorticoids.
Provided early diagnosis of metabolic disorders and diabetes mellitus, adequate therapy can alleviate a person’s condition.
With excessive secretion of insulin, men are at risk of impotence, patients of any gender experience vision problems, asthma, bronchitis, hypertension, premature baldness, and the likelihood of myocardial infarction, atherosclerosis, acne and dandruff increases.
If too much insulin is produced, the pancreas itself suffers and becomes overgrown with fat.
Insulin, glucagon
Sugar level
To normalize metabolic processes in the body, it is necessary to take pancreatic hormones. They should be used strictly as prescribed by the endocrinologist.
Classification of pancreatic hormone preparations: short-acting, medium-acting, long-acting. The doctor may prescribe a specific type of insulin or recommend a combination of both.
Indications for prescribing short-acting insulin are diabetes mellitus and excessive amounts of sugar in the bloodstream when sweetener tablets do not help. These products include Insuman, Rapid, Insuman-Rap, Actrapid, Homo-Rap-40, Humulin.
The doctor will also offer the patient medium-term insulins: 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 the body of 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, keep the conversion of non-carbohydrate foods into sugar under control, and increase glycemic levels 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 levels, 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, there must be a normal supply of proteins, fats, peptides, carbohydrates and amino acids.
Somatostatin, vasointense 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 to inhibit the biological synthesis of pancreatic enzymes, lower glucagon levels, and inhibit 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 gastrin secretion, inhibit blood flow in the abdominal cavity, and peristalsis of the digestive tract.
Vasointense peptide
This neuropeptide hormone is secreted by cells of various organs: the back and brain, small intestine, pancreas. The level of the substance in the bloodstream is quite low and remains almost unchanged after eating. The main functions of the hormone include:
- activation of blood circulation in the intestines;
- inhibition of the release of hydrochloric acid;
- acceleration of bile excretion;
- inhibition of water absorption by the intestine.
In addition, there is stimulation of somatostatin, glucagon and insulin, and the launch of the production of pepsinogen in the cells of the stomach. In the presence of an inflammatory process in the pancreas, a disruption in the production of neuropeptide hormone begins.
Another substance produced by the gland is 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 optimize the amount of monosaccharides; it prevents increased amounts 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, the oxidation of fatty acids, enhances the effect of lipotropic compounds, and becomes a measure for the prevention of fatty liver degeneration.
The hormone kallikrein is produced by the pancreas, but remains in an inactive state there; it begins to work only after entering the duodenum. It lowers glycemic levels and lowers blood 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 intestinal phase of digestion.
Substance centroptein of protein nature:
- stimulates 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 pancreatic hormone preparations appear on the market, their presentation is carried out, which makes it easier to solve such disorders, and they have fewer and fewer contraindications.
Pancreatic hormones play a key role in regulating the body’s vital functions, so it is necessary to have an idea of 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 exocrine and endocrine gland. The incretory function is performed by the islet apparatus. The 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 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 manner (insulin lowers and glucagon increases). Insufficiency of the endocrine function of the pancreas is manifested by symptoms of insulin deficiency (and therefore it is considered to be the main hormone of the pancreas).
Insulin is a polypeptide consisting of two chains - A and B, connected by two disulfide bridges. Chain A consists of 21 amino acid residues, chain B - 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 chains of insulin, and the C-protein chain connecting them, consisting of 35 amino acid residues. After the cleavage of C-protein and the addition of 4 amino acid residues, insulin molecules are formed, which are packaged into granules and undergo exocytosis. Insulin incretion has a pulsatile nature with a period of 15-30 minutes. During the day, 5 mg of insulin is released into the systemic circulation, 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 secretion insulin (3-cells. Somatostatin produced by D-cells inhibits, and some amino acids (phenylalanine), fatty acids, glucagon, amylin and glucose enhance the release of insulin. In this case, the level of glucose in the blood plasma is the determining factor in the regulation of insulin secretion. Glucose enters the (3-cell and triggers a chain of metabolic reactions, as a result of which the ATP concentration increases in the (3-cells). This substance blocks ATP-dependent potassium channels and the membrane (3-cells comes into a state of depolarization. As a result of depolarization, the opening frequency increases voltage-gated calcium channels The concentration of calcium ions in β-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 insulin's influence 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, fat, and glycogen is enhanced), while the influence of insulin on carbohydrate metabolism is of primary importance.
It is extremely important to note that those indicated in table. 31.1 changes in tissue metabolism are accompanied by a decrease in plasma glucose levels (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 through facilitated diffusion (energy-independent transport along an electrochemical gradient through special transport systems). Facilitated glucose diffusion systems are called GLUTs. Indicated in the table. 31.1 adipocytes and striated muscle fibers contain GLUT 4, through which glucose enters “insulin-dependent” tissues.
Table 31.1. The effect of insulin on metabolism
The effect 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 outside of the membranes of insulin-dependent tissues and have binding centers for insulin molecules, and the p-subunits represent 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. While the insulin molecule is bound to the receptor, the receptor remains in an activated state and stimulates phosphorylation processes. After the dimer dissociates, 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 GLUT synthesis. This can be represented schematically as follows (Fig. 31.1):
With insufficient production of endogenous insulin, diabetes mellitus occurs. Its main symptoms are hyperglycemia, glycosuria, polyuria, polydipsia, ketoacidosis, angiopathy, etc.
Insulin deficiency can be absolute (an autoimmune process leading to the death of the islet apparatus) and relative (in 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). For both forms of diabetes, a diet is indicated. The procedure for prescribing pharmacological drugs for different forms of diabetes is not the same.
Antidiabetic drugs
Used for 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 pork insulin. In addition, there is a genetically engineered method for producing human insulin. Insulin preparations obtained from the pancreas of slaughter cattle may contain impurities of proinsulin, C-protein, glucagon, and somatostatin. Modern technologies for
make it possible to obtain highly purified (monocomponent), crystallized and monopeak (chromatographically purified to isolate the “peak” of insulin) drugs.
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 subject to proteolysis in the systemic circulation, insulin has a short duration of action, and therefore 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 poorly soluble crystals. When administered subcutaneously, 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 the long latency period, so they are sometimes combined with non-long-acting insulin preparations. This combination ensures rapid development of the effect and its sufficient duration.
Insulin preparations are classified according to their 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).
- Medium-acting insulin (onset after 1.5-2 hours, peak after
- 12 hours, total duration 8-12 hours).
- Intermediate-acting insulin in combinations.
Side effects. Currently, either genetically engineered human insulins or highly purified pork insulins are used in medical practice. In this regard, complications of insulin therapy are relatively rare. Allergic reactions and lipodystrophy at the injection site are possible. If too high doses of insulin are administered or if the intake of dietary carbohydrates is insufficient, excessive hypoglycemia may develop. Its extreme variant is hypoglycemic coma with loss of consciousness, convulsions and symptoms of cardiovascular failure. In case of hypoglycemic coma, the patient should be administered intravenously a 40% glucose solution in an amount of 20-40 (but not more than 100) ml.
Since insulin drugs are used lifelong, it should be borne in mind that their hypoglycemic effect may be modified by other drugs. Strengthen the hypoglycemic effect of insulin: α-blockers, β-blockers, tetracyclines, salicylates, disopyramide, anabolic steroids, sulfonamides. Weaken the hypoglycemic effect of insulin: p-adrenomimetics, sympathomimetics, glucocorticosteroids, thiazide diuretics.
Contraindications: diseases accompanied by 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 rapid action in 10 ml bottles (1 ml of solution contains 40 or 100 IU of insulin). It can be produced in cartridges (Actrapid NM Penfill) for use in the Novo-Pen insulin syringe 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. Bottles of 10 ml suspension (40 IU in 1 ml). The hypoglycemic effect begins after 1-2 hours, reaches a maximum after 6-12 hours, and lasts 18-24 hours.
Monotard NM is a composite suspension of human zinc insulin (contains 30% amorphous and 70% crystalline zinc insulin. Bottles of 10 ml of suspension (40 or 100 IU in 1 ml). The hypoglycemic effect begins after
- h, reaches a maximum after 7-15 h, lasts 24 h.
Porcine insulin preparations
Insulin neutral for injection (InsulinS, ActrapidMS) is a neutral solution of monopeak or monocomponent porcine insulin of short and rapid action. Bottles of 5 and 10 ml (1 ml of solution contains 40 or 100 IU 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 subcutaneously, 15 minutes before meals, the initial dose is from 8 to 24 IU (IU). , the highest single dose is 40 units. To relieve diabetic coma, it is administered intravenously.
Insulin isophane is a monopeak monocomponent pork isophane protamine insulin. The hypoglycemic effect begins after 1-3 hours, reaches a maximum after 3-18 hours, and lasts about 24 hours. It is most often used as a component of combination drugs 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). Bottles of 10 ml 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). Bottles of 10 ml of 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.
