What is insulin made of? Which organ and how produces insulin, mechanism of action

between each other by two disulfide bridges (Fig. 11-23). Insulin can exist in several forms: monomer, dimer, and hexamer. The hexameric structure of insulin is stabilized by zinc ions, which are bound by His residues at position 10 of the B chain of all 6 subunits.

The insulin molecule also contains an intramolecular disulfide bridge connecting the sixth and eleventh residues in the A chain. The insulins of some animals have a significant similarity in primary structure with human insulin.

Bovine insulin differs from human insulin by three amino acid residues, while porcine insulin differs by only one amino acid, which is represented by alanine instead of threonine at the carboxyl end of the B chain.

Rice. 11-23. The structure of human insulin. A. Primary structure of insulin. B. Model of the tertiary structure of insulin (monomer): 1 - A-chain; 2 - B-chain; 3 - receptor binding site.

In both chains, substitutions occur in many positions that do not affect the biological activity of the hormone. Most often, these substitutions are found in positions 8, 9, and 10 of the A chain.

At the same time, substitutions in the positions of disulfide bonds, hydrophobic amino acid residues in the C-terminal regions of the B-chain and C- and N-terminal residues of the A-chain are very rare, which indicates the importance of these regions for the manifestation of the biological activity of insulin. The use of chemical modifications and amino acid substitutions in these regions made it possible to establish the structure active center insulin, in the formation of which the phenylalanine residues of the B chain in positions 24 and 25 and the N- and C-terminal residues of the A chain take part.

biosynthesis of insulin includes the formation of two inactive precursors, preproinsulin and proinsulin, which, as a result of sequential proteolysis, are converted into an active hormone. The biosynthesis of preproinsulin begins with the formation of a signal peptide on polyribosomes associated with the ER. The signal peptide penetrates the ER lumen and directs the entry of the growing polypeptide chain into the ER lumen. After preproinsulin synthesis is completed, the signal peptide, which includes 24 amino acid residues, is cleaved off (Fig. 11-24).

Proinsulin (86 amino acid residues) enters the Golgi apparatus, where, under the action of specific proteases, it is cleaved in several sites to form insulin (51 amino acid residues) and a C-peptide consisting of 31 amino acid residues.

Rice. 11-24. Scheme of insulin biosynthesis inβ cells of the islets of Langerhans. ER - endoplasmic reticulum. 1 - signal peptide formation; 2 - synthesis of preproinsulin; 3 - signal peptide cleavage; 4 - transport of proinsulin to the Golgi apparatus; 5 - conversion of proinsulin to insulin and C-peptide and incorporation of insulin and C-peptide into secretory granules; 6 - secretion of insulin and C-peptide.

Insulin and C-peptide are incorporated into secretory granules in equimolar amounts. In granules, insulin combines with zinc to form dimers and hexamers. Mature granules fuse with the plasma membrane and insulin and C-peptide are secreted into the extracellular fluid by exocytosis. After secretion into the blood, insulin oligomers break down. T 1/2 insulin in blood plasma is 3-10 minutes, C-peptide - about 30 minutes.

The destruction of insulin occurs under the action of the enzyme insulinase mainly in the liver and to a lesser extent in the kidneys.

Regulation of insulin synthesis and secretion. Glucose is the main regulator of insulin secretion, and β-cells are the most important glucose-sensitive cells in the body. Glucose regulates the expression of the insulin gene, as well as the genes of other proteins involved in the metabolism of the main energy carriers. The effect of glucose on the rate of gene expression can be direct, when glucose directly interacts with transcription factors, or secondary, through its effect on the secretion of insulin and glucagon. When stimulated with glucose, insulin is rapidly released from secretory granules, which is accompanied by activation of insulin mRNA transcription.

Synthesis and secretion of insulin are not strictly coupled processes. The synthesis of the hormone is stimulated by glucose, and its secretion is a Ca 2+ -dependent process, and in case of Ca 2+ deficiency it decreases even in conditions of high glucose concentration, which stimulates insulin synthesis.

Glucose consumption by β-cells occurs mainly with the participation of GLUT-1 and GLUT-2, and the concentration of glucose in the cells quickly equalizes with the concentration of glucose in the blood. In β-cells, glucose is converted into glucose-6-phosphate by glucokinase, which has a high Kt, as a result of which the rate of its phosphorylation almost linearly depends on the concentration of glucose in the blood. The glucokinase enzyme is one of the most important components of the glucose-sensitive apparatus of β-cells, which, in addition to glucose, probably includes intermediate products of glucose metabolism, the citrate cycle, and, possibly, ATP. Mutations in glucokinase lead to the development of a form of diabetes mellitus.

Insulin secretion is influenced by other hormones. Adrenaline through α 2 receptors inhibits insulin secretion even against the background of glucose stimulation, β-adrenergic agonists stimulate it, probably as a result of an increase in cAMP concentration. This mechanism is believed to underlie the action of gastrointestinal hormones such as secretin, cholecystokinin, and gastric inhibitory peptide (GIP), which increase insulin secretion. High concentrations of growth hormone, cortisol, and estrogens also stimulate insulin secretion.

Which organ and how produces insulin, mechanism of action

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All diabetics know what it is and what it is needed to lower blood glucose levels. But what is its structure, what organ produces insulin and what is the mechanism of action? This will be discussed in this article. Dedicated to the most curious diabetics…

Which organ produces insulin in the human body

The human organ responsible for the production of the hormone insulin is pancreas. The main function of the gland is endocrine.

The answer to the question: “What or what human organ produces insulin” is the pancreas.

Thanks to the pancreatic islets (Langerhans), 5 types of hormones are produced, most of which regulate "sugar affairs" in the body.

• a cells - produce glucagon (stimulates the breakdown of liver glycogen into glucose, maintaining sugar levels at a constant level)
• b cells - produce insulin
• d cells - synthesizes somatostatin (capable of reducing the production of insulin and pancreatic glucagon)
• G cells - gastrin is produced (regulates the secretion of somastotin, and participates in the work of the stomach)
• PP cells - produce pancreatic polypeptide (stimulates the production of gastric juice)

Most of the cells are beta cells (b cells), which are located mainly at the tip and head of the gland, and secrete the diabetic hormone insulin.

The answer to the question: "What does the pancreas produce besides insulin" - hormones for the stomach.

The composition of insulin, the structure of the molecule

As we can see in the figure, the insulin molecule consists of two polypeptide chains. Each chain is made up of amino acid residues. Chain A contains 21 residues, chain B contains 30. In addition, insulin consists of 51 amino acid residue. The chains are connected into one molecule by disulfide bridges that form between cysteine ​​residues.

Interestingly, in pigs, the structure of the insulin molecule is almost the same, the only difference is in one residue - instead of threonine, pigs have alanine in chain B. It is because of this similarity that porcine insulin is often used for injections. By the way, bovine is also used, but it already differs by 3 residues, which means it is less suitable for the human body.

Insulin production in the body, mechanism of action, properties

Insulin is produced by the pancreas when blood glucose levels rise.

Hormone formation can be divided into several stages:

• Initially, an inactive form of insulin is formed in the gland - preproinsulin . It consists of 110 amino acid residues created by combining four peptides - L, B, C and A.
• Next, preproinsulin is synthesized into the endoplasmic reticulum. In order to pass through the membrane, the L-peptide, which consists of 24 residues, is cleaved off. Thus arises proinsulin.
• Proinsulin enters the Golgi complex, where it will continue its maturation. During maturation, the C-peptide (consisting of 31 residues) is separated, which connected the B and A peptides. At this point, the proinsulin molecule splits into two polypeptide chains, forming the necessary molecule insulin .

How Insulin Works

In order to release insulin from granules, in which it is now stored, you need to inform the pancreas about the increase in blood glucose levels. To do this, there is a whole chain of interrelated processes that are activated when sugar increases.

• Glucose in the cell undergoes glycolysis and forms adenosine triphosphate (ATP).
• ATP controls the closure of potassium ion channels, causing depolarization of the cell membrane.
• Depolarization opens calcium channels, causing a perceptible influx of calcium into the cell.
• The granules in which insulin is stored respond to this increase and release the required amount of insulin. The release takes place with exocytosis. That is, the granule merges with the cell membrane, zinc, which fettered the activity of insulin, is split off, and active insulin enters the human body.

Thus, the human body receives the necessary regulator of blood glucose.

What is insulin responsible for, the role in the human body

The hormone insulin is involved in all metabolic processes in the human body. But its most important role is carbohydrate metabolism. The effect of insulin on carbohydrate metabolism is to transport glucose directly into the cells of the body. Fat and muscle tissues, which make up two-thirds of human tissue, are insulin dependent. Without insulin, glucose cannot enter their cells. In addition, insulin also:

• regulates the absorption of amino acids
• regulates the transport of potassium, magnesium and phosphate ions
• enhances the synthesis of fatty acids
• reduces protein breakdown

Very interesting video about insulin below.

The answer to the question: “Why do we need insulin in the body” is the regulation of carbohydrate and other metabolic processes in the body.

Conclusions

In this article, I tried to tell as clearly as possible which organ produces insulin, the production process, and how the hormone acts on the human body. Yes, I had to use some complex terms, but without them it would not have been possible to fully cover the topic. But now you can see what a really complex process of the appearance of insulin, its work and impact on our health.

DISORDERS OF CARBOHYDRATE METABOLISM.

The pathology of carbohydrate metabolism can be represented by a combination of catabolic disorders and anabolic transformations carbohydrates.

Carbohydrate catabolism disorders:

1. Violation of digestion and absorption of carbohydrates in the intestine.
2. Dysfunction of the liver, which leads to a violation of gluconeogenesis and glycogenolysis and the conversion of glucose into pyruvic acid, catalyzed by glycolysis enzymes.
3. Violation of glucose catabolism in peripheral cells.

Disorders of carbohydrate anabolism are manifested by violations of the synthesis and deposition of glycogen in the liver (glycogenesis). Violations of this process are noted during hypoxia.

The most common cause of carbohydrate metabolism disorders is disturbance of neurohormonal regulation.

There is some evidence that the nervous system is involved in the regulation of blood glucose.

So, Claude Bernard first showed that an injection into the bottom of the IV ventricle leads to hyperglycemia ("sugar injection"). An increase in the concentration of glucose in the blood can lead to irritation of the gray tubercle of the hypothalamus, the lenticular nucleus and the striatum of the basal nuclei of the brain. Cannon observed that mental overstrain, emotions can increase the level of glucose in the blood. Hyperglycemia also occurs with painful sensations, during epilepsy attacks, etc.

Today it has been proven that nervous system on blood glucose levels is mediated by a number of hormones. The following options are possible:

1. CNS → sympathetic nervous system → adrenal medulla → adrenaline → hyperglycemia (C. Bernard injection).
2. CNS → parasympathetic nervous system → pancreatic islets → insulin and glucagon.
3. CNS → sympathetic nervous system → adrenal medulla → adrenaline → pancreatic islet β-cells → inhibition of insulin secretion.
4. CNS → hypothalamus → adenohypophysis → ACTH → glucocorticoids → hyperglycemia.

Violation of the hormonal regulation of carbohydrate metabolism can occur not only in violation of central mechanisms regulation of the activity of the corresponding endocrine glands, but also with pathology themselves glands or at violation of the peripheral mechanisms of action of hormones.

Hormones involved in the regulation of carbohydrate metabolism are divided into two groups : insulin and contrainsular hormones.

contrinsular called hormones, which by their biological effects are insulin antagonists. These include adrenaline, glucagon, glucocorticoids, corticotropin, growth hormone, thyroid hormones.

The leading factor in the violation of the hormonal regulation of carbohydrate metabolism is change in the ratio between the activity of insulin and contrainsular hormones. Insulin deficiency and the predominance of the influence of contrainsular hormones are accompanied by hyperglycemia.

Insulin.

depending on insulin sensitivity structures organisms are divided into three groups :

1. Completely dependent on insulin. These include the liver, muscles (skeletal, myocardium), adipose tissue.
2. Absolutely insensitive. These are the brain, adrenal medulla, erythrocytes, testes.
3. Relatively sensitive(all other organs and tissues).

Biological effects of insulin.

1. Hypoglycemic action . Insulin reduces blood glucose levels by:

a) inhibition of processes that ensure the release of glucose from the liver into the blood (glycogenolysis and glyconeogenesis);

b) increased use of glucose by insulin-dependent tissues (muscle, fat);

2 Anabolic action . Insulin stimulates lipogenesis in adipose tissue, glycogenesis in the liver, and protein biosynthesis in muscles.

3. Mitogenic action . At high doses, insulin stimulates cell proliferation in vivo and in vitro.

Depending on the rate of occurrence effects of insulin divided into:

1. Very fast(occur within seconds) - a change in the membrane transport of glucose, ions.
2. Fast(minutes last) - allosteric activation of anabolic enzymes and inhibition of catabolism enzymes.
3. Slow(last from several minutes to several hours) - induction of the synthesis of anabolic enzymes and repression of the synthesis of catabolism enzymes.
4. Very slow(from several hours to several days) - mitogenic effect.

Control hormones.

Under the influence adrenaline increases the content of glucose in the blood. This effect is based on the following mechanisms:

1. Activation of glycogenolysis in the liver. It is associated with the activation of the adenylate cyclase system of hepatocytes and the formation, ultimately, of the active form of phosphorylase.
2. Activation of glycogenolysis in muscles followed by activation of gluconeogenesis in the liver. In this case, lactic acid, released from muscle tissue into the blood, goes to the formation of glucose in hepatocytes.
3. Inhibition of glucose uptake by insulin-dependent tissues with simultaneous activation of lipolysis in adipose tissue.
4. Suppression of insulin secretion by β-cells and stimulation of glucagon secretion by α-cells of pancreatic islets.

Usually, adrenaline hyperglycemia is short-lived, but with tumors of the adrenal medulla (pheochromocytoma), it is more permanent.

Glucagon , released under the influence of sympathetic stimulation of β-adrenergic receptors of α-cells of the pancreatic islets also contributes to hyperglycemia. This effect is based on the following mechanisms:

1. Activation of glycogenolysis in the liver.
2. Activation of gluconeogenesis in hepatocytes.

Both mechanisms are cAMP-mediated.

The group of contrainsular hormones also includes glucocorticoids . They activate the processes of gluconeogenesis in the liver, increasing:

a) synthesis of the corresponding enzymes (influence on transcription);

increased proteolysis in muscles.

In addition, glucocorticoids reduce glucose uptake by insulin-dependent tissues.

Corticotropin acts similarly to glucocorticoids, since by stimulating the release of glucocorticoids, it enhances gluconeogenesis and inhibits the activity of hexokinase.

Increased production of the adenohypophysis hormone - growth hormone (growth hormone), for example, with acromegaly, is accompanied by the development of insulin resistance of muscles and adipose tissue - they become insensitive to the action of insulin. The result of this is hyperglycemia.

Thyroid hormones also involved in the regulation of carbohydrate metabolism. It is known that hyperfunction of the thyroid gland is characterized by a decrease in the body's resistance to carbohydrates. Thyroxine stimulates the absorption of glucose in the intestines, and also enhances the activity of phosphorylase in the liver.

The hyperglycemic action of adrenaline lasts up to 10 minutes, glucagon - 30-60 minutes, glucocorticoids - from several hours to several days, somatotropic hormone - weeks, months, years.

With an increase in insulin levels, hypoglycemia develops, and with a decrease in its concentration, hyperglycemia develops.

With an increase in the content of contrainsular hormones, hyperglycemia develops, and with a decrease, hypoglycemia develops.

The state of regulation of carbohydrate metabolism, the ability of the body to absorb a certain amount of carbohydrates is judged by tolerance to carbohydrates , which is determined using glucose load. In a healthy person, after taking 50 g of glucose on an empty stomach for one hour, the blood glucose level reaches its maximum figures, exceeding the initial one by 50-75% (approximately 8.0-8.8 mmol / l). By the end of the second hour after taking glucose, its level in the blood returns to normal.

Carbohydrate tolerance determines that maximum amount glucose, which the body can absorb without the appearance of glycosuria. In humans, this is 160-180 g of glucose taken on an empty stomach. With reduced tolerance to carbohydrates glycosuria develops from a smaller amount of glucose consumed. In general, glycosuria appears when the blood glucose level exceeds the renal threshold - 8 mmol / l (according to some authors 10 mmol / l). With a high concentration of glucose in the blood, the enzymatic systems responsible for the process of glucose reabsorption in the renal tubules (hexokinase, phosphatase) do not provide phosphorylation of all glucose and part of it is excreted in the urine.

In some cases, glycosuria appears without hyperglycemia. This may be due to disruption of the process of glucose phosphorylation in the kidneys, for example, with the introduction of phloridzin (a glycoside from the bark of fruit trees), which inhibits phosphorylation. In violation of the enzymatic processes in the kidneys, which are the basis of glucose reabsorption, renal diabetes develops.

hypoglycemia - this is a decrease in the concentration of glucose in the blood plasma to a level that causes the appearance of clinical symptoms that disappear after the normalization of the content of this substance.

Signs of hypoglycemia appear, as a rule, when the glucose content drops below 4 mol / l.

Mechanisms of hypoglycemia:

1. Decreased supply of glucose to the blood. This happens with starvation, indigestion (deficiency of amylolytic enzymes, absorption disorders), with hereditary and acquired disorders of glycogenolysis and gluconeogenesis in the liver.
2. Increased use of glucose on the energy needs of the body (for example, hard physical work).
3. Loss of glucose(glycosuria) or misuse (malignant tumors).

Clinical signs of hypoglycemia are associated with two groups of disorders in the body:

1. Impaired supply of glucose to the brain. Depending on the degree of hypoglycemia, symptoms such as headache, inability to concentrate, fatigue, inappropriate behavior, hallucinations, convulsions, hypoglycemic coma.
2. Activation of the sympathoadrenal system. This causes palpitations, increased sweating, trembling, and a feeling of hunger.

Hypoglycemic coma is the most severe consequence of hypoglycemia and, if timely assistance is not provided (glucose administration), leads to death. It is characterized by loss of consciousness, loss of reflexes, violations of vital functions. Hypoglycemic coma develops when the level of glucose in blood plasma falls below 2.5 mmol/l.

Hyperglycemia - this is an increase in plasma glucose over 6.66 mmol / l as determined by the Hagedorn-Jensen method.

Mechanisms of hyperglycemia:

1. Increasing the entry of glucose into the blood. This happens after a meal (alimentary hyperglycemia), with an increase in glycogenolysis and gluconeogenesis in the liver (a decrease in insulin or an increase in the concentration of contrainsular hormones).
2. Impaired use of glucose s peripheral tissues. So, with a decrease in the content of insulin, the intake and utilization of glucose in insulin-dependent tissues (muscles, adipose tissue, liver) is disrupted.

Diabetes - a disease resulting from absolute or relative insulin deficiency, accompanied by a metabolic disorder, mainly carbohydrate.

Diabetes is a disease that, in an untreated state, manifests itself as a chronic increase in blood glucose - hyperglycemia (WHO definition, 1987).

Diabetes mellitus occurs in 1-4% of the population.

The main manifestations of diabetes- hyperglycemia, sometimes reaching 25 mmol / l, glycosuria with glucose in the urine up to 555-666 mmol / day. (100-120 g / day), polyuria (up to 10-12 liters of urine per day), polyphagia and polydipsia. An increase in the level of lactic acid (lactocidemia) is also characteristic - more than 0.8 mmol / l (the norm is 0.033-0.78 mmol / l); lipemia - 50-100 g / l (norm 3.5-8.0 g / l), sometimes ketonemia (by definition of acetone) with an increase in the level of ketone bodies up to 5200 μmol / l (the norm is less than 517 μmol / l).

Experimental Models diabetes mellitus:

1. Pancreatic diabetes - removal of 9/10 pancreas in dogs (Mehring and Minkowski, 1889).
2. Alloxan diabetes mellitus- a single injection of alloxan to animals - a substance that selectively damages β-cells of the pancreatic islets.
3. streptozotocin diabetes mellitus- administration of an antibiotic to animals - streptozotocin, which selectively damages β-cells of the pancreatic islets.

Insulin is a protein made up of two peptide chains A(21 amino acids) and V(30 amino acids) linked by disulfide bridges. A total of 51 amino acids are present in mature human insulin and its molecular weight is 5.7 kDa.

Synthesis

Insulin is synthesized in β-cells of the pancreas in the form of preproinsulin, at the N-terminus of which there is a terminal signal sequence of 23 amino acids, which serves as a conductor of the entire molecule into the cavity of the endoplasmic reticulum. Here, the terminal sequence is immediately cleaved off and proinsulin is transported to the Golgi apparatus. At this stage, the proinsulin molecule contains A chain, B-chain and C-peptide(English) connecting- binder). In the Golgi apparatus, proinsulin is packaged into secretory granules along with the enzymes needed to "mature" the hormone. As the granules move to plasma membrane disulfide bridges are formed, the binding C-peptide (31 amino acids) is cut out and the finished molecule is formed insulin. In the finished granules, insulin is in a crystalline state in the form of a hexamer formed with the participation of two Zn 2+ ions.

Regulation of synthesis and secretion

Insulin secretion is continuous, and about 50% of the insulin released from β-cells is unrelated to food intake or other influences. During the day, the pancreas secretes approximately 1/5 of the reserves of insulin available in it.

The main stimulant secretion of insulin is an increase in the concentration of glucose in the blood above 5.5 mmol / l, secretion reaches a maximum at 17-28 mmol / l. A feature of this stimulation is a biphasic increase in insulin secretion:

• first phase lasts 5-10 minutes and the concentration of the hormone can increase 10-fold, after which its amount decreases,
• second phase begins approximately 15 minutes after the onset of hyperglycemia and continues throughout its entire period, leading to an increase in the level of the hormone by 15-25 times.

The longer a high concentration of glucose remains in the blood, the moreβ-cells are connected to the secretion of insulin.

Fusion induction insulin occurs from the moment glucose enters the cell to the translation of insulin mRNA. It is regulated by increased transcription of the insulin gene, increased stability of insulin mRNA, and increased translation of insulin mRNA.

Secretion activation insulin

1. After glucose enters β-cells (through GluT-1 and GluT-2), it is phosphorylated by hexokinase IV (glucokinase, has a low affinity for glucose),
2. Further, glucose is aerobically oxidized, while the rate of glucose oxidation depends linearly on its amount,
3. As a result, ATP is produced, the amount of which also directly depends on the concentration of glucose in the blood,
4. The accumulation of ATP stimulates the closure of ionic K + -channels, which leads to membrane depolarization,
5. Depolarization of the membrane leads to the opening of voltage-dependent Ca 2+ channels and the influx of Ca 2+ ions into the cell,
6. Incoming Ca 2+ ions activate phospholipase C and trigger the calcium-phospholipid signal transduction mechanism with the formation of DAG and inositol triphosphate (IF 3),
7. The appearance of IF 3 in the cytosol opens Ca 2+ channels in the endoplasmic reticulum, which accelerates the accumulation of Ca 2+ ions in the cytosol,
8. A sharp increase in the concentration of Ca 2+ ions in the cell leads to the movement of secretory granules to the plasma membrane, their fusion with it and exocytosis of mature insulin crystals to the outside,
9. Next, the crystals disintegrate, Zn 2+ ions are separated, and active insulin molecules are released into the bloodstream.

Scheme of intracellular regulation of insulin synthesis with the participation of glucose

The described driving mechanism can be adjusted in one direction or another under the influence of a number of other factors, such as amino acids, fatty acids, hormones GI tract and other hormones nervous regulation.

Of the amino acids, hormone secretion is most significantly affected by lysine and arginine. But by themselves, they almost do not stimulate secretion, their effect depends on the presence of hyperglycemia, i.e. amino acids only potentiate the action of glucose.

Free fatty acids are also factors stimulating insulin secretion, but also only in the presence of glucose. In hypoglycemia, they have the opposite effect, suppressing the expression of the insulin gene.

Logical is the positive sensitivity of insulin secretion to the action of hormones of the gastrointestinal tract - incretins(enteroglucagon and glucose-dependent insulinotropic polypeptide), cholecystokinin, secretin, gastrin, gastric inhibitory polypeptide.

Clinically important and to some extent dangerous is the increase in insulin secretion during prolonged exposure. growth hormone, ACTH and glucocorticoids, estrogen, progestins. This increases the risk of depletion of β-cells, a decrease in insulin synthesis and the occurrence of insulin-dependent diabetes mellitus. This can be observed when these hormones are used in therapy or in pathologies associated with their hyperfunction.

Nervous regulation of pancreatic β-cells includes adrenergic and cholinergic regulation. Any stress (emotional and/or physical stress, hypoxia, hypothermia, injury, burns) increases the activity of the sympathetic nervous system and inhibits insulin secretion by activating α2-adrenergic receptors. On the other hand, stimulation of β 2 -adrenergic receptors leads to increased secretion.

Insulin secretion also increases n.vagus , which in turn is under the control of the hypothalamus, which is sensitive to the concentration of blood glucose.

targets

Insulin receptors are found on almost all cells of the body, except nerve cells, but in different amount. Nerve cells do not have insulin receptors, because the latter simply does not cross the blood-brain barrier.

The highest concentration of receptors is observed on the membrane of hepatocytes (100-200 thousand per cell) and adipocytes (about 50 thousand per cell), a skeletal muscle cell has about 10 thousand receptors, and erythrocytes - only 40 receptors per cell.

Mechanism of action

After insulin binds to the receptor, it is activated enzymatic domain receptor. Since he has tyrosine kinase activity, it phosphorylates intracellular proteins - substrates of the insulin receptor. Further development events are due to two directions: MAP-kinase pathway and phosphatidylinositol-3-kinase mechanisms of action.

When activated phosphatidylinositol-3-kinase mechanisms result are quick effects– activation of GluT-4 and the entry of glucose into the cell, changes in the activity of "metabolic" enzymes - TAG-lipase, glycogen synthase, glycogen phosphorylase, glycogen phosphorylase kinase, acetyl-SCoA-carboxylase and others.

When implementing MAP-kinase mechanism (English) mitogen-activated protein) are regulated slow effects– cell proliferation and differentiation, processes of apoptosis and anti-apoptosis.

Two mechanisms of action of insulin

The rate of action of insulin

The biological effects of insulin are classified according to the rate of development:

Very fast effects (seconds)

These effects are related to the change transmembrane transports:

1. Activation of Na + /K + -ATPase, which causes the release of Na + ions and the entry of K + ions into the cell, which leads to hyperpolarization membranes of insulin-sensitive cells (except hepatocytes).

2. Activation of the Na + /H + -exchanger on the cytoplasmic membrane of many cells and the release of H + ions from the cell in exchange for Na + ions. This effect is important in the pathogenesis of arterial hypertension in type 2 diabetes mellitus.

3. Inhibition of membrane Ca 2+ -ATPase leads to retention of Ca 2+ ions in the cytosol of the cell.

4. Exit to the membrane of myocytes and adipocytes of GluT-4 glucose carriers and an increase in the volume of glucose transport into the cell by 20-50 times.

Quick effects (minutes)

Quick effects are speed changes phosphorylation and dephosphorylation metabolic enzymes and regulatory proteins.

Liver

• braking the effects of adrenaline and glucagon (phosphodiesterase),
• acceleration glycogenogenesis(glycogen synthase),
• activation glycolysis
• conversion of pyruvate to acetyl-SCoA(PVC-dehydrogenase),
• gain fatty acid synthesis(acetyl-SCoA-carboxylase),
• formation VLDL,
• promotion cholesterol synthesis(HMG-SCoA reductase),

muscles

• braking effects of adrenaline (phosphodiesterase),
• Glut-4),
• stimulation glycogenogenesis(glycogen synthase),
• activation glycolysis(phosphofructokinase, pyruvate kinase),
• conversion of pyruvate to acetyl-SCoA(PVC-dehydrogenase),
• enhances the transport of neutral amino acids into the muscles
• stimulates broadcast(ribosomal protein synthesis).

Adipose tissue

• stimulates the transport of glucose into cells (activation Glut-4),
• activates the storage of fatty acids in tissues ( lipoprotein lipase),
• activation glycolysis(phosphofructokinase, pyruvate kinase),
• gain fatty acid synthesis(activation of acetyl-SCoA-carboxylase),
• creating an opportunity for storage of TAG(inactivation of hormone-sensitive-lipase).

Slow effects (minutes-hours)

Slow effects consist in changing the rate of transcription of protein genes responsible for metabolism, cell growth and division, for example:

1. Induction enzyme synthesis in the liver

• glucokinase and pyruvate kinase (glycolysis),
• ATP citrate lyase, acetyl SCoA carboxylase, fatty acid synthase, cytosolic malate dehydrogenase ( fatty acid synthesis),
• glucose-6-phosphate dehydrogenase ( pentose phosphate pathway),

2. Induction in adipocytes for the synthesis of glyceraldehyde phosphate dehydrogenase and fatty acid synthase.

3. Repression mRNA synthesis, for example, for PEP-carboxykinase ( gluconeogenesis).

4. Provides processes broadcasts, increasing serine phosphorylation of the ribosomal protein S6.

Very slow effects (hours-days)

Very slow effects realize mitogenesis and cell reproduction. For example, these effects include

1. Increase in the synthesis of somatomedin in the liver, dependent on growth hormone.

2. Increased growth and proliferation of cells in synergy with somatomedins.

3. Cell transition from the G1 phase to the S phase of the cell cycle.

It is the group of slow effects that explains the "paradox" of the presence of insulin resistance of adipocytes (in type 2 diabetes mellitus) and the simultaneous increase in the mass of adipose tissue and the accumulation of lipids in it under the influence of hyperglycemia and insulin.

Insulin inactivation

Removal of insulin from the circulation occurs after its binding to the receptor and subsequent internalization (endocytosis) of the hormone-receptor complex, mainly in liver and muscles. After absorption, the complex is destroyed and protein molecules lysed to free amino acids. In the liver, up to 50% of insulin is captured and destroyed during the first passage of blood flowing from the pancreas. V kidneys insulin is filtered into the primary urine and, after reabsorption in the proximal tubules, is destroyed.

Pathology

Hypofunction

Insulin-dependent and non-insulin dependent diabetes mellitus. For the diagnosis of these pathologies in the clinic, stress tests and the determination of the concentration of insulin and C-peptide are actively used.