What is glucagon, functions and norm of the hormone. Functions of glucagon in the human body High concentrations of glucose inhibit glucagon production

Even before insulin was discovered, various groups of cells were found in the islets of the pancreas.

The hormone glucagon itself was discovered by Merlin and Kimball in 1923, but few people were interested in this discovery at that time, and only 40 years later it became clear that this hormone plays a vital physiological role in the metabolism of ketone bodies and glucose.

However, its role as a drug is currently insignificant.

Chemical properties

Glucagon is a single-chain polypeptide consisting of 29 amino acid residues. Significant homology has been discovered between glucagon and other hormones of a polypeptide nature, such as

1. secretin,
2. gas inhibitory peptide,

The amino acid sequence of this hormone is similar in many mammals and is the same in pigs, humans, rats and cows; it is a pancreatic hormone.

The physiological function and role of glucagon precursor peptides have not yet been clarified. But there is an assumption, based on the complex regulation of preproglucagon processing, that they all have special functions.

The cells of the pancreatic islets have secretory granules, in which a central core consisting of glucagon and an outer rim of glycentin are distinguished. L cells located in the intestine contain granules consisting only of glycentin.

Most likely, these pancreatic cells lack the enzyme that converts glycentin into glucagon.

Oxyntomodulin stimulates adenylate cyclase by binding to glucagon receptors located on hepatocytes. The activity of this peptide is about 20% of that of glucagon.

Glucagon-like protein of the first type very strongly activates the release of insulin, but has virtually no effect on hepatocytes.

Glycentin, glucagon-like peptides and oxyntomodulin are found mainly in the intestine. After removal of the pancreas, glucagogue secretion continues.

Regulation of secretion

The secretion of glucagon, and its synthesis action, for which food glucose is responsible, as well as insulin, fatty acids and amino acids. Glucose is a powerful inhibitor of glucagon formation.

It has a stronger effect on the secretion and synthesis of this hormone when taken orally than when administered intravenously, as indicated by its instructions for use.

Glucose acts in the same way on the release of insulin. Most likely, this effect is associated with the action of digestive hormones and is lost in poorly compensated diabetes mellitus (insulin-dependent) or in the absence of its treatment.

It is not present in a-cell culture either. That is, we can conclude that the effect of glucose on a-cells, to some extent, depends on its activation of insulin secretion. The secretion and level of glucagon are also inhibited by free fatty acids, somatostatin and ketone bodies.

Most amino acids enhance the secretion of both insulin and the action of glucagon. That is why, after eating a meal consisting only of proteins, a person does not experience insulin-mediated hypoglycemia and all pancreatic functions continue to function normally.

Like glucose, amino acids have a greater effect when taken orally than when administered by injection. That is, their effect is partly due to digestive hormones. In addition, the release of glucagon is controlled by the autonomic nervous system.

The secretion and synthesis of this hormone is enhanced by stimulation of the sympathetic nerve fibers responsible for the innervation of the pancreatic islets, as well as by the administration of sympathomimetics and adrenergic stimulants.

Metabolism and synthesis of glucagon are based on the following principles:

• Glucagon undergoes rapid destruction in the liver, plasma and kidneys, as well as in some target tissues.
• Its half-life in plasma is only 3-6 minutes.
• The hormone loses its biological activity when the N-terminal histidine residue is cleaved by proteases.

Mechanism of action

Glucagon binds to a special receptor located on the membrane of target cells. This receptor is a glycoprotein with a specific molecular weight.

It has not yet been possible to completely decipher its structure, but it is known that it is associated with the Gj protein, which activates adenylate cyclase and affects its synthesis.

The main effect of glucagon on hepatocytes occurs through cyclic AMP. Due to modification of the N-terminal region of the glucagon molecule, it is converted into a partial agonist.

While the affinity for the receptor is maintained, its ability to activate adenylate cyclase is largely lost. This behavior is typical for des-His-[Glu9]-glucagonamide and [Fen]-glucagon.

This enzyme determines the intracellular concentration of fructose-2,6-diphosphate, which affects glycogenolysis and gluconeogenesis.

If the level of glucagon is high and synthesis occurs quickly, then with a small amount of insulin, phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-diphosphatase occurs and it begins to work as a phosphatase.

At the same time, the amount of fructose-2,6-biphosphate in the liver decreases. When insulin concentrations are high and glucagon is low, the enzyme begins to dephosphorylate and functions as a kinase to increase fructose 2,6-bisphosphate levels.

This compound leads to the activation of phosphofructokinase, an enzyme that accelerates the rate-limiting reaction of glycolysis.

Thus, at a high concentration of glucagon, glycolysis is inhibited and gluconeogenesis is enhanced, and at a high insulin content, glycolysis is activated. Ketogenesis and gluconeogenesis are suppressed.

Application

Glucagon, as well as its synthesis, is intended to relieve severe attacks of hypoglycemia when it is impossible to administer intravenous glucose infusion. The instructions for using the hormone describe everything quite clearly

This usually occurs in diabetic patients. This hormone is also used in radiation diagnostics to suppress the motility of the digestive tract. In this case, there are alternatives to using the hormone.

Glucagon, used in medicine, is isolated from the pancreas of pigs or cows. This is due to the fact that the amino acids of glucagon are arranged in the same order in these animals. For hypoglycemia, the hormone is administered intramuscularly, intravenously or subcutaneously in an amount of 1 mg

In emergency cases, it is better to use glucagon and the first two routes of administration. After 10 minutes, improvement occurs, which minimizes the risk of central nervous system diseases.

Under the influence of glucagon, it is short-lived, and may not occur at all if glycogen reserves in the liver are insufficient. After the patient's condition returns to normal, the patient needs to eat something or get a glucose injection to prevent a recurrent attack of hypoglycemia. The most common adverse reactions to glucagon are vomiting and nausea.

1. This hormone is prescribed before X-ray examination of parts of the gastrointestinal tract, before MRI and retrograde ideography to relax the muscles of the intestines and stomach and improve their function.
2. Glucagon is used to relieve spasms in diseases of the biliary tract and sphincter of Oddi or in acute diverticulitis.
3. As an auxiliary element in removing stones from the gall bladder using the Dormia loop, as well as in intussusception and obstructive processes in the esophagus and improving their function.
4. Glucagon secretion is used as an experimental diagnostic tool for pheochromocytoma, as it activates the release of catecholamines by the cells of this tumor.
5. This hormone is used to treat shock because it has an inotropic effect on the heart. It is effective in patients taking beta-blockers, because adrenergic stimulants do not work in such cases.

Unger postulated that metabolic disorders in diabetes are not determined solely by insulin deficiency, but that diabetes is a bihormonal disorder in which relative or absolute hyperglucagonemia is important. Evidence for the importance of changes in glucagon secretion in the pathogenesis of diabetes has been obtained from various studies. In diabetic patients, glucose does not suppress glucagon secretion, but the introduction of protein or amino acids causes its hypersecretion (Fig. 10-34). In contrast, the glucagon response to hypoglycemia is reduced in patients with type I diabetes, indicating a defect in glucose receptors on the surface of α-cells. In addition, pancreatectomy-induced diabetes in experimental animals is accompanied by excessive production of extrapancreatic glucagon. Further, the decrease in plasma glucagon levels caused by somatostatin leads to a decrease in the severity of diabetic hyperglycemia.

Despite the appeal of the bihormonal theory, some data raise serious doubts about the relevance of glucagon or primary α-cell dysfunction in spontaneous diabetes in humans. Increasing the plasma glucagon level (induced by infusion of this hormone) to the level found in diabetes or other conditions accompanied by hyperglucagonemia does not impair glucose tolerance in healthy individuals and does not reduce the degree of glycemic compensation in diabetic patients as long as they receive insulin. In individuals with a removed pancreas, extrapancreatic glucagon is not produced, but hyperglycemia and ketosis still develop. Similarly, long-term suppression of glucagon and insulin secretion by somatostatin causes transient hypoglycemia followed by fasting hyperglycemia and excess glucose production (i.e., the diabetic state), despite continued suppression of glucagon secretion. In patients with insulin-dependent diabetes, in whom somatostatin significantly reduces glucose levels after meals, this effect is determined mainly by inhibition of the absorption of carbohydrates and proteins, and not by an increase in carbohydrate utilization. Finally, treatment with insulin leads to the elimination of hyperglucagonemia in human diabetes and to the restoration of α-cell function in experimental diabetes.

Thus, the main role of glucagon in diabetes is that it enhances the effects of insulin deficiency. According to this, food-induced secretion of glucagon in a patient with uncompensated diabetes increases the degree of hyperglycemia after eating. In addition, hyperglucagonemia in diabetic ketoacidosis enhances ketogenesis in the liver.

Glucagon plays a primary role in the development of hyperglycemia in patients with glucagonoma syndrome (see below).

Rice. 10-34. The influence of protein foods on the level of glucagon in plasma and glucose production by the abdominal organs (liver) in healthy individuals (1) and patients with insulin-dependent (type I) diabetes (2). The insulin content in the patients' plasma was not determined, since they had previously received it. Protein foods caused a pronounced increase in glucose production in diabetic patients, but not in healthy individuals. This difference was a consequence of an excessive increase in plasma glucagon levels against the background of absolute insulin deficiency (according to Wharen J., Felig P., Hagenfeldt L., J. Clin. Invest., 1976, 57, 987).

Glucagon is a protein-peptide hormone that is produced in the islet apparatus of the pancreas. Special alpha cells of the organ are responsible for its synthesis, synthesizing exclusively these compounds. Glucagon (like cortisol and somatotropin) is a counter-insular hormone, that is, it has the opposite effect on carbohydrate metabolism than insulin. The production of glucagon is necessary to maintain adequate blood glucose levels, however, excess production of this hormone is one of the mechanisms for the development of type 2 diabetes.

Mechanism of action of glucagon

Glucagon's functions in the body are limited but very important. It increases blood glucose levels by activating glycogenolysis. Glycogen is a polysaccharide consisting of glucose monomer, found primarily in the liver and muscles.

When carbohydrates are consumed in the gastrointestinal tract, they are broken down. The glucose obtained during digestion under the influence of insulin is converted into glycogen, which is a “reserve depot” necessary to maintain an adequate level of glycemia in the event of a lack of carbohydrates in food or an increase in the need for them (during physical activity).

When the glycemic level decreases, counterinsular hormones are produced and released into the blood, which increase glucose levels in different ways. One of them is glucagon, the mechanism of action of which is to activate the enzymes necessary for glycogenolysis, resulting in the formation of glucose from glycogen, which is consumed by cells as an energy substrate.

Hormones responsible for carbohydrate metabolism are capable of regulating each other's secretion. An increase in glucagon levels leads to an increase in the concentration of insulin in the blood.

Diseases associated with disruption of hormone effects

At the moment, only one disease is known in the pathogenesis of which the role of glucagon has been reliably determined - type 2 diabetes mellitus. With this pathology, hormone synthesis increases, which leads to excessive activation of glycogenolysis and an increase in glycemia levels. It is worth noting that an increase in glucagon levels is only one of many links in the pathogenesis of diabetes and is far from the most significant.

The concentration of glucagon in the blood is not determined to diagnose diabetes mellitus. To date, laboratory criteria and reference intervals have not been developed to clearly distinguish normal indicators from diabetes mellitus. In addition, the level of the hormone increases with renal and liver failure, which makes this study unreliable.

There are hypoglycemic drugs, the mechanism of action of which is associated, among other things, with the suppression of glucagon secretion (type 1 glucagon-like peptide agonists, dipeptidyl peptidase-4 inhibitors).

Secondary diabetes mellitus can be the result of excessive secretion of the hormone - a tumor of the pancreas (glucogonoma). In this disease, glycogen levels are several times higher than the population average. In addition to carbohydrate metabolism disorders, pancytopenia, necrolytic migratory erythema, symptoms of metastatic damage to the liver and other internal organs (excruciating pain) are recorded. The tumor is usually detected quite late, at a stage that is not subject to surgical treatment.

Glycogen-based drug

There is a glucagon drug on the pharmaceutical market. The drug is intended to relieve hypoglycemia. These conditions occur predominantly in patients with diabetes mellitus who are on insulin therapy or taking sulfonylureas.

The drug is available in finished form in a container connected to a syringe and can be used for subcutaneous, intramuscular or intravenous injections. The possibility of subcutaneous and intramuscular administration makes this drug suitable for self-help (or for administration by the patient’s relatives).

Glucagon preparation

For a body weight of 20 kg or more, 1 mg of the drug is administered, for a lower weight - 500 mcg.

Glucagon is contraindicated for:

• pheochromocytoma;
• insulinoma;
• glucagonoma;
• individual intolerance.

Possible side effects:

• vomiting, nausea;
• skin rashes and itching;
• arterial hypertension, sinus tachycardia.

It is worth noting that the administration of the drug to relieve hypoglycemia is effective only in the presence of glycogen in the liver. Treatment of hypoglycemic conditions in fasting patients or patients eating only protein and significantly limiting carbohydrate intake is not effective with this drug.

An important organ of our body is the pancreas. It produces several hormones that affect the body's metabolism. These include glucagon, a substance that releases glucose from cells. In addition to it, the pancreas generates somatostatin and pancreatic polypeptide. Somatostatin is responsible for limiting the production of somatotropin and catecholamines (adrenaline, norepinephrine). The peptide regulates the functioning of the gastrointestinal tract. Insulin and glucagon control the content of the main source of energy - glucose, and these 2 hormones are directly opposite in action. What is glucagon and what other functions does it have, we will answer in this article.

Glucagon production and activity

Glucagon is a peptide substance that is produced by the islets of Langerhans and other cells of the pancreas. The parent of this hormone is preproglucagon.

Glucose obtained by the body from food has a direct effect on the synthesis of glucagon. Protein products taken by a person during meals also affect the synthesis of the hormone. They contain arginine and alanine, which increase the amount of the described substance in the body.

Glucagon synthesis is affected by physical work and sports. The greater the load, the greater the synthesis of the hormone. It also begins to be intensively produced during fasting. As a protective agent, the substance is produced during times of stress. Its surge is affected by the rise in level and .

Glucagon serves to form glucose from amino acids in proteins. Thus, it provides all organs of the human body with the energy necessary for functioning. The functions of glucagon include:

• the breakdown of glycogen in the liver and muscles, due to which the supply of glucose stored there is released into the blood and serves for energy metabolism;
• the breakdown of lipids (fats), which also leads to the energy supply of the body;
• formation of glucose from non-carbohydrate products;
• ensuring increased blood supply to the kidneys;
• increased blood pressure;
• increased heart rate;
• antispasmodic effect;
• increased content of catecholamines;
• stimulation of liver cell recovery;
• accelerating the process of removing sodium and phosphorus from the body;
• regulation of magnesium metabolism;
• increase in calcium content in cells;
• removal of insulin from cells.

It should be noted that in muscles, glucagon does not stimulate the production of glucose, since they do not have the necessary receptors that respond to the hormone. But from the list it is clear that the role of the substance in our body is quite large.

Glucagon and insulin are 2 opposing hormones. Insulin serves to store glucose in cells. It is produced when glucose levels are high, storing it in reserve. The mechanism of action of glucagon is that it releases glucose from cells and sends it to the organs of the body for energy metabolism. We must also take into account that some human organs absorb glucose, despite the functioning of insulin. These include the brain of the head, the intestines (some of its parts), the liver, and both kidneys. In order for the metabolism of sugar in the body to be balanced, other hormones are also needed - this is cortisol, the fear hormone adrenaline, which affects the growth of bones and tissues.

Hormone norm and deviations from it

The level of the hormone glucagon depends on the age of the person. In adults, the spread between the lower and upper values ​​is smaller. The table looks like this:

Deviation from the norm in the volume of the hormone may indicate pathology. Including, when determining a reduced amount of a substance, the following are possible:

• severe cystic fibrosis of the endocrine glands and respiratory organs;
• chronic inflammation of the pancreas;
• A decrease in glucagon levels occurs after operations to remove the pancreas.

The functions of glucagon are to eliminate some of the pathologies described above. An increased content of a substance indicates one of the situations:

• increased glucose due to type 1 diabetes mellitus;
• tumor lesion of the pancreas;
• acute inflammation of the pancreas;
• liver cirrhosis (degeneration of cells into tumor tissue);
• excessive production of glucocorticoids due to their generation by tumor cells;
• chronic kidney failure;
• psychological stress.

If the hormone is exceeded or decreased, the doctor prescribes other tests for an accurate diagnosis. Blood biochemistry is done to determine glucagon levels.

Glucagon-containing agents

Glucagon is synthesized from the hormone of animals, taking advantage of the fact that they have this substance of a similar structure. The medicine is available in the form of liquid for injection and in the form of tablets for oral administration. Injections are given intravenously or intramuscularly. The drug is prescribed in the following cases:

• diabetes mellitus with low glucose levels;
• additional treatment for depression;
• the need to relieve spasm of the intestines;
• to soothe and straighten smooth muscles;
• for diseases of the biliary tract;
• during radiological examination of the stomach.

The instructions describe that the dose of the injection, which is administered intravenously or, if it is impossible to inject a vein, intramuscularly, is 1 ml. After the injection, an increase in hormone levels, accompanied by an increase in the amount of glucose, is observed after 10 minutes.

The drug can be used to treat children. If the baby's weight is less than 20 kg, the dose should be no more than 0.5 ml. For heavier children, the dosage ranges from 0.5 to 1 ml. If the effect of the medication is insufficient, the injection is repeated after 12 minutes. You need to inject in a different place.

Treatment of children and pregnant women can only be carried out in a clinic under the supervision of a specialist. In preparation for radiation diagnostics, 0.25 mg to 2 mg of medication is injected. The dose, depending on the patient’s condition and weight, is calculated by the doctor. Taking the drug in any form without a doctor’s prescription is strictly prohibited.

If the medicine is being used as an emergency, after taking it, you should eat protein foods, drink a cup of warm, sweetened tea, and go to bed for 2 hours.

Contraindications to treatment with Glucagon

Glucagon should not be used for treatment in the following cases:

• tumor disease of the pancreas with the production of insulin by tumor cells;
• high sugar content;
• with a benign or malignant tumor (pheochromocytoma), the cells of which generate catecholamines;
• in case of individual intolerance to the drug.

Additional diagnostic procedures are required for early detection of contraindications to hormone treatment. Side effects from taking Glucagon may include nausea and vomiting. If the use of the medicine does not give the expected result, it is necessary to administer a glucose solution to the patient.

The drug can be used to treat pregnant women. It is retained by the placenta and does not reach the fetus. During the feeding period, the use of the drug is possible only under the strict supervision of a specialist.

If glucose is below normal, what to do?

Before the doctor arrives, you can increase your glucose level by eating certain foods. It's a good idea to eat 50 g of honey, which contains fructose, glucose and sucrose of natural origin. After all, only artificial fructose is harmful. And, if glucagon and glucose are not produced in sufficient quantities to supply us with glucose, it is necessary to take sugar in the form of food.

Tea with jam will help restore strength. After severe overload or nervous stress, it is useful to eat heavily with high-calorie foods. Their list includes seafood, nuts, apples, cheeses, pumpkin seeds, and vegetable oils. Rest in a ventilated room and sound sleep will bring benefits.

Pancreas- the second largest iron, its mass is 60-100 g, length 15-22 cm.

The endocrine activity of the pancreas is carried out by the islets of Langerhans, which consist of different types of cells. Approximately 60% of the pancreatic islets are β cells. They produce a hormone insulin, which affects all types of metabolism, but primarily reduces glucose levels in.

Table. Pancreatic hormones

Insulin(polypeptide) is the first protein produced synthetically outside the body in 1921 by Baylis and Bunty.

Insulin dramatically increases the permeability of the muscle and fat cell membrane to glucose. As a result, the rate of glucose transfer into these cells increases approximately 20 times compared to the transfer of glucose into cells in the absence of insulin. In muscle cells, insulin promotes the synthesis of glycogen from glucose, and in fat cells - fat. Under the influence of insulin, permeability also increases for amino acids, from which proteins are synthesized in cells.

Rice. The main hormones that affect blood glucose levels

Second pancreatic hormone glucagon- secreted by islet a-cells (approximately 20%). Glucagon is a polypeptide in chemical nature, and an insulin antagonist in physiological effects. Glucagon enhances the breakdown of glycogen in the liver and increases plasma glucose levels. Glucagon promotes the mobilization of fat from fat depots. A number of hormones act like glucagon: growth hormone, glucocorticoids, adrenaline, thyroxine.

Table. Main effects of insulin and glucagon

The third hormone of the pancreas is somatostatin secreted by 5 cells (approximately 1-2%). Somatostatin inhibits the release of glucagon and the absorption of glucose in the intestine.

Hyper- and hypofunction of the pancreas

When pancreatic hypofunction occurs diabetes. It is characterized by a number of symptoms, the occurrence of which is associated with an increase in blood sugar - hyperglycemia. An increased content of glucose in the blood, and therefore in the glomerular filtrate, leads to the fact that the epithelium of the renal tubules does not completely reabsorb glucose, so it is excreted in the urine (glucosuria). There is a loss of sugar in the urine - sugar urination.

The amount of urine is increased (polyuria) from 3 to 12, and in rare cases up to 25 liters. This is because unreabsorbed glucose increases the osmotic pressure of urine, which retains water in the urine. Water is not sufficiently absorbed by the tubules, and the amount of urine excreted by the kidneys is increased. Dehydration causes diabetic patients to become very thirsty, which leads to copious amounts of water (about 10 liters). Due to the excretion of glucose in the urine, the consumption of proteins and fats as substances that provide energy metabolism in the body increases sharply.

Weakening of glucose oxidation leads to impaired fat metabolism. Products of incomplete oxidation of fats are formed - ketone bodies, which leads to a shift in the blood to the acidic side - acidosis. Accumulation of ketone bodies and acidosis can cause a serious, life-threatening condition - diabetic coma, which occurs with loss of consciousness, impaired breathing and circulation.

Pancreatic hyperfunction is a very rare disease. Excessive insulin in the blood causes a sharp decrease in blood sugar - hypoglycemia which can lead to loss of consciousness - hypoglycemic coma. This is explained by the fact that the central nervous system is very sensitive to a lack of glucose. The introduction of glucose relieves all these phenomena.

Regulation of pancreatic function. Insulin production is regulated by a negative feedback mechanism depending on the concentration of glucose in the blood plasma. Increased blood glucose levels increase insulin production; Under conditions of hypoglycemia, insulin formation, on the contrary, is inhibited. Insulin production may increase when the vagus nerve is stimulated.

Endocrine function of the pancreas

Pancreas(weight in an adult 70-80 g) has a mixed function. The acinar tissue of the gland produces digestive juice, which is excreted into the lumen of the duodenum. The endocrine function in the pancreas is performed by clusters (from 0.5 to 2 million) of cells of epithelial origin, called islets of Langerhans (Pirogov-Langerhans) and constituting 1-2% of its mass.

Paracrine regulation of cells of the islets of Langerhans

The islets contain several types of endocrine cells:

• a-cells (about 20%), forming glucagon;
• β-cells (65-80%), synthesizing insulin;
• δ-cells (2-8%), synthesizing somatostatin;
• PP cells (less than 1%), producing pancreatic polypeptide.

Young children have G cells that produce gastrins. The main hormones of the pancreas that regulate metabolic processes are insulin and glucagon.

Insulin- a polypeptide consisting of 2 chains (A-chain consists of 21 amino acid residues and B-chain - of 30 amino acid residues), interconnected by disulfide bridges. Insulin is transported in the blood mainly in a free state and its content is 16-160 µU/ml (0.25-2.5 ng/ml). During the day (3 cells of an adult healthy person produce 35-50 units of insulin (approximately 0.6-1.2 units/kg body weight).

Table. Mechanisms of glucose transport into the cell

Insulin secretion

Insulin secretion is divided into basal, which has a pronounced secretion, and stimulated by food.

Basal secretion ensures optimal levels of glucose in the blood and anabolic processes in the body during sleep and in the intervals between meals. It is about 1 unit/hour and accounts for 30-50% of daily insulin secretion. Basal secretion decreases significantly with prolonged physical activity or fasting.

Food-stimulated secretion is an increase in basal insulin secretion caused by food intake. Its volume is 50-70% of the daily allowance. This secretion ensures the maintenance of glucose levels in the blood in the face of additional intake from the intestine and makes it possible for it to be effectively absorbed and utilized by cells. The severity of secretion depends on the time of day and has a two-phase character. The amount of insulin secreted into the blood approximately corresponds to the amount of carbohydrates taken and is 1-2.5 units of insulin for every 10-12 g of carbohydrates (in the morning 2-2.5 units, at lunch - 1-1.5 units, in the evening - about 1 unit ). One of the reasons for this dependence of insulin secretion on the time of day is the high level of counter-insular hormones (primarily cortisol) in the blood in the morning and its decrease in the evening.

Rice. Mechanism of insulin secretion

The first (acute) phase of stimulated insulin secretion does not last long and is associated with exocytosis by β-cells of the hormone already accumulated during the period between meals. It is caused by the stimulating effect on β-cells not so much of glucose as of gastrointestinal hormones - gastrin, enteroglucagon, glycentin, glucagon-like peptide 1, secreted into the blood during food intake and digestion. The second phase of insulin secretion is due to the stimulating effect on β-cells of glucose itself, the level of which in the blood increases as a result of its absorption. This action and increased insulin secretion continue until the glucose level reaches normal for a given person, i.e. 3.33 - 5.55 mmol/l in venous blood and 4.44 - 6.67 mmol/l in capillary blood.

Insulin acts on target cells by stimulating 1-TMS membrane receptors with tyrosine kinase activity. The main target cells of insulin are liver hepatocytes, skeletal muscle myocytes, and adipose tissue adipocytes. One of its most important effects is a decrease in blood glucose levels; insulin realizes through increased absorption of glucose from the blood by target cells. This is achieved by activating the work of transmembrane glucose transporters (GLUT4), embedded in the plasma membrane of target cells, and increasing the rate of glucose transfer from the blood to the cells.

Insulin is metabolized 80% in the liver, the rest in the kidneys and in small quantities in muscle and fat cells. Its half-life from the blood is about 4 minutes.

Main effects of insulin

Insulin is an anabolic hormone and has a number of effects on target cells in various tissues. It has already been mentioned that one of its main effects, a decrease in blood glucose levels, is realized by increasing its absorption by target cells, accelerating the processes of glycolysis and carbohydrate oxidation in them. A decrease in glucose levels is facilitated by insulin stimulation of glycogen synthesis in the liver and muscles, suppression of gluconeogenesis and glycogenolysis in the liver. Insulin stimulates the uptake of amino acids by target cells, reduces catabolism and stimulates protein synthesis in cells. It also stimulates the conversion of glucose into fats, the accumulation of triacylglycerols in adipocytes of adipose tissue and suppresses lipolysis in them. Thus, insulin has a general anabolic effect, enhancing the synthesis of carbohydrates, fats, proteins and nucleic acids in target cells.

Insulin also has a number of other effects on cells, which, depending on the speed of manifestation, are divided into three groups. Quick effects are realized within seconds after the hormone binds to the receptor, for example, the absorption of glucose, amino acids, and potassium by cells. Slow effects unfold within minutes from the onset of the hormone’s action - inhibition of the activity of protein catabolism enzymes, activation of protein synthesis. Delayed effects insulin begins hours after it binds to receptors - DNA transcription, mRNA translation, acceleration of cell growth and reproduction.

Rice. Mechanism of action of insulin

The main regulator of basal insulin secretion is glucose. An increase in its content in the blood to a level above 4.5 mmol/l is accompanied by an increase in insulin secretion according to the following mechanism.

Glucose → facilitated diffusion with the participation of the GLUT2 transporter protein into the β-cell → glycolysis and accumulation of ATP → closure of ATP-sensitive potassium channels → exit delay, accumulation of K+ ions in the cell and depolarization of its membrane → opening of voltage-gated calcium channels and the entry of Ca 2 ions + into the cell → accumulation of Ca2+ ions in the cytoplasm → increased exocytosis of insulin. Insulin secretion is stimulated in the same way by increasing blood levels of galactose, mannose, β-keto acid, arginine, leucine, alanine and lysine.

Rice. Regulation of insulin secretion

Hyperkalemia, sulfonylurea derivatives (drugs for the treatment of type 2 diabetes), blocking potassium channels of the plasma membrane of β-cells, increase their secretory activity. Increase insulin secretion: gastrin, secretin, enteroglucagon, glycentin, glucagon-like peptide 1, cortisol, growth hormone, ACTH. An increase in insulin secretion by acetylcholine is observed when the parasympathetic division of the ANS is activated.

Inhibition of insulin secretion is observed during hypoglycemia, under the influence of somatostatin and glucagon. Catecholamines, released when the activity of the SNS increases, have an inhibitory effect.

Glucagon - peptide (29 amino acid residues) produced by the a-cells of the islet apparatus of the pancreas. It is transported in the blood in a free state, where its content is 40-150 pg/ml. It has its effects on target cells by stimulating 7-TMS receptors and increasing the level of cAMP in them. The half-life of the hormone is 5-10 minutes.

Contrinsular action of glucogon:

• Stimulates β-cells of the islets of Langerhans, increasing insulin secretion
• Activates liver insulinase
• Has antagonistic effects on metabolism

Scheme of a functional system that maintains optimal metabolic blood glucose levels

Main effects of glucagon in the body

Glucagon is a catabolic hormone and an insulin antagonist. In contrast to insulin, it increases blood glucose levels by enhancing glycogenolysis, suppressing glycolysis and stimulating gluconeogenesis in liver hepatocytes. Glucagon activates lipolysis, causes an increased flow of fatty acids from the cytoplasm into the mitochondria for their β-oxidation and the formation of ketone bodies. Glucagon stimulates protein catabolism in tissues and increases urea synthesis.

Glucagon secretion increases with hypoglycemia, decreased levels of amino acids, gastrin, cholecystokinin, cortisol, and growth hormone. Increased secretion is observed with increased activity and stimulation of β-AR by catecholamines. This occurs during physical activity and fasting.

Glucagon secretion is inhibited by hyperglycemia, excess fatty acids and ketone bodies in the blood, as well as by the action of insulin, somatostatin and secretin.

Disorders of endocrine pancreatic function can manifest themselves in the form of insufficient or excessive secretion of hormones and lead to sudden disturbances in glucose homeostasis - the development of hyper- or hypoglycemia.

Hyperglycemia - This is an increase in blood glucose levels. It can be acute or chronic.

Acute hyperglycemia most often it is physiological, as it is usually caused by the entry of glucose into the blood after eating. Its duration usually does not exceed 1-2 hours due to the fact that hyperglycemia suppresses the release of glucagon and stimulates insulin secretion. When the blood glucose level increases above 10 mmol/l, it begins to be excreted in the urine. Glucose is an osmotically active substance, and its excess is accompanied by an increase in the osmotic pressure of the blood, which can lead to cell dehydration, the development of osmotic diuresis and loss of electrolytes.

Chronic hyperglycemia, in which elevated blood glucose levels persist for hours, days, weeks or more, can cause damage to many tissues (especially blood vessels) and is therefore considered a pre-pathological and/or pathological condition. It is a characteristic symptom of a whole group of metabolic diseases and dysfunction of the endocrine glands.

One of the most common and severe among them is diabetes(DM), which affects 5-6% of the population. In economically developed countries, the number of patients with diabetes doubles every 10-15 years. If diabetes develops as a result of impaired insulin secretion by β-cells, it is called type 1 diabetes mellitus—DM-1. The disease can also develop when the effectiveness of insulin on target cells decreases in older people, and it is called type 2 diabetes mellitus (DM-2). At the same time, the sensitivity of target cells to the action of insulin decreases, which can be combined with a violation of the secretory function of β-cells (loss of the 1st phase of food secretion).

A common symptom of DM-1 and DM-2 is hyperglycemia (increased fasting venous blood glucose levels above 5.55 mmol/l). When blood glucose levels rise to 10 mmol/L or more, glucose appears in the urine. It increases the osmotic pressure and volume of final urine and this is accompanied by polyuria (an increase in the frequency and volume of urine excreted to 4-6 l/day). The patient develops thirst and increased fluid consumption (polydipsia) due to increased osmotic pressure of blood and urine. Hyperglycemia (especially with DM-1) is often accompanied by the accumulation of products of incomplete oxidation of fatty acids - hydroxybutyric and acetoacetic acids (ketone bodies), which is manifested by the appearance of a characteristic odor of exhaled air and (or) urine, and the development of acidosis. In severe cases, this can cause dysfunction of the central nervous system - the development of a diabetic coma, accompanied by loss of consciousness and death of the body.

Excessive insulin content (for example, during insulin replacement therapy or stimulation of its secretion with sulfonylurea drugs) leads to hypoglycemia. Its danger lies in the fact that glucose serves as the main energy substrate for brain cells, and when its concentration decreases or is absent, brain function is disrupted due to dysfunction, damage and (or) death of neurons. If low glucose levels persist long enough, death can occur. Therefore, hypoglycemia (when the blood glucose level decreases to less than 2.2-2.8 mmol/l) is considered as a condition in which a doctor of any specialty must provide first aid to the patient.

Hypoglycemia is usually divided into reactive, occurring after meals and on an empty stomach. The cause of reactive hypoglycemia is increased secretion of insulin after meals due to hereditary impaired tolerance to sugars (fructose or galactose) or changes in sensitivity to the amino acid leucine, as well as in patients with insulinoma (beta-cell tumor). The causes of fasting hypoglycemia can be insufficiency of the processes of glycogenolysis and (or) gluconeogenesis in the liver and kidneys (for example, with a deficiency of counterinsular hormones: glucagon, catecholamines, cortisol), excessive utilization of glucose by tissues, insulin overdose, etc.

Hypoglycemia manifests itself in two groups of symptoms. The state of hypoglycemia is a stress for the body, in response to the development of which the activity of the sympathoadrenal system increases, the level of catecholamines in the blood increases, which cause tachycardia, mydriasis, trembling, cold sweat, nausea, and a feeling of severe hunger. The physiological significance of the activation of the sympathoadrenal system by hypoglycemia is the activation of the neuroendocrine mechanisms of catecholamines for the rapid mobilization of glucose into the blood and normalization of its level. The second group of signs of hypoglycemia is associated with dysfunction of the central nervous system. They manifest themselves in a person as decreased attention, development of headaches, feelings of fear, disorientation, impaired consciousness, convulsions, transient paralysis, coma. Their development is due to a sharp lack of energy substrates in neurons, which cannot receive sufficient amounts of ATP when there is a lack of glucose. Neurons do not have mechanisms for storing glucose in the form of glycogen, like hepatocytes or myocytes.

A doctor (including a dentist) must be prepared for such situations and be able to provide first aid to patients with diabetes in the event of hypoglycemia. Before starting dental treatment, it is necessary to find out what diseases the patient suffers from. If he has diabetes, the patient should be asked about his diet, insulin doses used and usual physical activity. It should be remembered that the stress experienced during the treatment procedure is an additional risk for the development of hypoglycemia in the patient. Thus, the dentist should have sugar in any form ready - sugar packets, sweets, sweet juice or tea. If the patient shows signs of hypoglycemia, you must immediately stop the treatment procedure and if the patient is conscious, then give him sugar in any form by mouth. If the patient's condition worsens, immediate action should be taken to provide effective medical care.