Energy homeostasis provides the energy needs of tissues using various substrates. Because Carbohydrates are the main source of energy for many tissues and the only one for anaerobic tissues; regulation of carbohydrate metabolism is an important component of the body's energy homeostasis.
Regulation carbohydrate metabolism carried out at 3 levels:
central.
interorgan.
cellular (metabolic).
1. Central level of regulation of carbohydrate metabolism
The central level of regulation is carried out with the participation of the neuroendocrine system and regulates the homeostasis of glucose in the blood and the intensity of carbohydrate metabolism in tissues. The main hormones that maintain normal blood glucose levels of 3.3-5.5 mmol/l include insulin and glucagon. Glucose levels are also influenced by adaptation hormones - adrenaline, glucocorticoids and other hormones: thyroid, SDH, ACTH, etc.
2. Interorgan level of regulation of carbohydrate metabolism
Glucose-lactate cycle (Cori cycle) Glucose-alanine cycle
Glucose-lactate cycle does not require the presence of oxygen, always functions, ensures: 1) utilization of lactate formed under anaerobic conditions (skeletal muscles, red blood cells), which prevents lactic acidosis; 2) glucose synthesis (liver).
Glucose-alanine cycle functions in muscles during fasting. With glucose deficiency, ATP is synthesized due to the breakdown of proteins and the catabolism of amino acids under aerobic conditions, while the glucose-alanine cycle ensures: 1) removal of nitrogen from muscles in a non-toxic form; 2) glucose synthesis (liver).
3. Cellular (metabolic) level of regulation of carbohydrate metabolism
The metabolic level of regulation of carbohydrate metabolism is carried out with the participation of metabolites and maintains the homeostasis of carbohydrates within the cell. An excess of substrates stimulates their use, and products inhibit their formation. For example, excess glucose stimulates glycogenesis, lipogenesis and amino acid synthesis, while glucose deficiency stimulates gluconeogenesis. A deficiency of ATP stimulates glucose catabolism, and an excess, on the contrary, inhibits it.
IV. Pedagogical Faculty. Age characteristics of PFS and GNG, significance.
Lecture No. 10 Topic: Structure and metabolism of insulin, its receptors, glucose transport. Mechanism of action and metabolic effects of insulin.
Pancreatic hormones
The pancreas performs two important functions in the body: exocrine and endocrine. The exocrine function is performed by the acinar part of the pancreas; it synthesizes and secretes pancreatic juice. The endocrine function is performed by the cells of the islet apparatus of the pancreas, which secrete peptide hormones involved in the regulation of many processes in the body. 1-2 million islets of Langerhans make up 1-2% of the mass of the pancreas.
In the islet part of the pancreas, there are 4 types of cells that secrete different hormones: A- (or α-) cells (25%) secrete glucagon, B- (or β-) cells (70%) - insulin, D- (or δ- ) cells (<5%) - соматостатин, F-клетки (следовые количества) секретируют панкреатический полипептид. Глюкагон и инсулин в основном влияют на углеводный обмен, соматостатин локально регулирует секрецию инсулина и глюкагона, панкреатический полипептид влияет на секрецию пищеварительных соков. Гормоны поджелудочной железы выделяются в панкреатическую вену, которая впадает в воротную. Это имеет большое значение т.к. печень является главной мишенью глюкагона и инсулина.
The structure of insulin
Insulin is a polypeptide consisting of two chains. Chain A contains 21 amino acid residues, chain B contains 30 amino acid residues. There are 3 disulfide bridges in insulin, 2 connect the A and B chains, 1 connects residues 6 and 11 in the A chain.
Insulin can exist in the form of: 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.
Insulins of some animals have significant similarity in primary structure to human insulin. Bovine insulin differs from human insulin by 3 amino acids, while porcine insulin differs by only 1 amino acid ( ala instead of tre at the C end of the B-chain).
In many positions of the A and B chain there are substitutions that do not affect the biological activity of the hormone. In the positions of disulfide bonds, hydrophobic amino acid residues in the C-terminal regions of the B-chain and the C- and N-terminal residues of the A-chain, substitutions are very rare, because These areas ensure the formation of the active center of insulin.
Insulin biosynthesis involves the formation of two inactive precursors, preproinsulin and proinsulin, which, as a result of sequential proteolysis, are converted into the active hormone.
1. Preproinsulin (L-B-C-A, 110 amino acids) is synthesized on ER ribosomes; its biosynthesis begins with the formation of the hydrophobic signal peptide L (24 amino acids), which directs the growing chain into the lumen of the ER.
2. In the ER lumen, preproinsulin is converted into proinsulin upon cleavage of the signal peptide by endopeptidase I. The cysteines in proinsulin are oxidized to form 3 disulfide bridges, proinsulin becomes “complex” and has 5% of the activity of insulin.
3. “Complex” proinsulin (B-C-A, 86 amino acids) enters the Golgi apparatus, where, under the action of endopeptidase II, it is cleaved to form insulin (B-A, 51 amino acids) and C-peptide (31 amino acids).
4. Insulin and C-peptide are incorporated into secretory granules, where insulin combines with zinc to form dimers and hexamers. In the secretory granule the content of insulin and C-peptide is 94%, proinsulin, intermediates and zinc - 6%.
5. Mature granules fuse with the plasma membrane, and insulin and C-peptide enter the extracellular fluid and then into the blood. In the blood, insulin oligomers break down. 40-50 units are secreted into the blood per day. insulin, this accounts for 20% of its total reserve in the pancreas. Insulin secretion is an energy-dependent process that occurs with the participation of the microtubular-villous system.
Scheme of insulin biosynthesis in β-cells of the islets of Langerhans
ER - endoplasmic reticulum. 1 - formation of a signal peptide; 2 - synthesis of preproinsulin; 3 - cleavage of signal peptide; 4 - transport of proinsulin to the Golgi apparatus; 5 - conversion of proinsulin into insulin and C-peptide and incorporation of insulin and C-peptide into secretory granules; 6 - secretion of insulin and C-peptide.
The insulin gene is located on chromosome 11. 3 mutations of this gene have been identified; carriers have low insulin activity, hyperinsulinemia, and no insulin resistance.
Regulation of insulin synthesis and secretion
Insulin synthesis is induced by glucose and insulin secretion. Represses the secretion of fatty acids.
Insulin secretion is stimulated by: 1. glucose (main regulator), amino acids (especially leu and arg); 2. Gastrointestinal hormones (β-adrenergic agonists, via cAMP): GUI , secretin, cholecystokinin, gastrin, enteroglucagon; 3. long-term high concentrations of growth hormone, cortisol, estrogens, progestins, placental lactogen, TSH, ACTH; 4. glucagon; 5. increase in K + or Ca 2+ in the blood; 6. drugs, sulfonylurea derivatives (glibenclamide).
Under the influence of somatostatin, insulin secretion decreases. β-cells are also influenced by the autonomic nervous system. The parasympathetic part (cholinergic endings of the vagus nerve) stimulates the release of insulin. The sympathetic part (adrenaline through α 2 -adrenergic receptors) suppresses the release of insulin.
Insulin secretion occurs with the participation of several systems, in which the main role belongs to Ca 2+ and cAMP.
Admission Sa 2+ into the cytoplasm is controlled by several mechanisms:
1). When the concentration of glucose in the blood increases above 6-9 mmol/l, it, with the participation of GLUT-1 and GLUT-2, enters β-cells and is phosphorylated by glucokinase. In this case, the concentration of glucose-6ph in the cell is directly proportional to the concentration of glucose in the blood. Glucose-6ph is oxidized to form ATP. ATP is also formed during the oxidation of amino acids and fatty acids. The more glucose, amino acids, and fatty acids there are in the β-cell, the more ATP is formed from them. ATP inhibits ATP-dependent potassium channels on the membrane, potassium accumulates in the cytoplasm and causes depolarization of the cell membrane, which stimulates the opening of voltage-dependent Ca 2+ channels and the entry of Ca 2+ into the cytoplasm.
2). Hormones that activate the inositol triphosphate system (TSH) release Ca 2+ from mitochondria and the ER.
cAMP is formed from ATP with the participation of AC, which is activated by the gastrointestinal hormones, TSH, ACTH, glucagon and Ca 2+ -calmodulin complex.
cAMP and Ca 2+ stimulate the polymerization of subunits into microtubules (microtubules). The effect of cAMP on the microtubular system is mediated through phosphorylation of PC A microtubular proteins. Microtubules are able to contract and relax, moving granules towards the plasma membrane allowing exocytosis.
Insulin secretion in response to glucose stimulation is a biphasic reaction consisting of a stage of rapid, early insulin release, called the first secretion phase (starts after 1 minute, lasts 5-10 minutes), and the second phase (lasts up to 25-30 minutes) .
Insulin transport. Insulin is water soluble and has no carrier protein in plasma. T1/2 of insulin in blood plasma is 3-10 minutes, C-peptide - about 30 minutes, proinsulin 20-23 minutes.
Insulin destruction occurs under the action of insulin-dependent proteinase and glutathione-insulin transhydrogenase in target tissues: mainly in the liver (about 50% of insulin is destroyed in 1 pass through the liver), to a lesser extent in the kidneys and placenta.
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The main energy resources of a living organism - carbohydrates and fats - have a high supply of potential energy, which is easily extracted from them in cells using enzymatic catabolic transformations. The energy released during the biological oxidation of the products of carbohydrate and fat metabolism, as well as glycolysis, is converted to a large extent into the chemical energy of the phosphate bonds of the synthesized ATP.
The chemical energy of macroergic bonds accumulated in ATP, in turn, is spent on various types of cellular work - the creation and maintenance of electrochemical gradients, muscle contraction, secretory and some transport processes, biosynthesis of protein, fatty acids, etc. In addition to the “fuel” function, carbohydrates and fats, along with proteins, play the role of important suppliers of building and plastic materials included in the main structures of the cell - nucleic acids, simple proteins, glycoproteins, a number of lipids, etc.
ATP synthesized due to the breakdown of carbohydrates and fats not only provides cells with the energy necessary for work, but is also a source of cAMP formation, and is also involved in the regulation of the activity of many enzymes and the state of structural proteins, ensuring their phosphorylation.
Carbohydrate and lipid substrates directly utilized by cells are monosaccharides (primarily glucose) and non-esterified fatty acids (NEFA), as well as ketone bodies in some tissues. Their sources are food products absorbed from the intestine, deposited in organs in the form of carbohydrate glycogen and lipids in the form of neutral fats, as well as non-carbohydrate precursors, mainly amino acids and glycerol, which form carbohydrates (gluconeogenesis).
The storage organs in vertebrates include the liver and adipose (adipotic) tissue, and the organs of gluconeogenesis include the liver and kidneys. In insects, the storage organ is the fat body. In addition, some reserve or other products stored or produced in a working cell can be sources of glucose and NEFA. Different pathways and stages of carbohydrate and fat metabolism are interconnected by numerous mutual influences. The direction and intensity of these metabolic processes depend on a number of external and internal factors. These include, in particular, the quantity and quality of food consumed and the rhythms of its entry into the body, the level of muscle and nervous activity, etc.
The animal organism adapts to the nature of the nutritional regime, to the nervous or muscular load with the help of a complex set of coordinating mechanisms. Thus, control of the course of various reactions of carbohydrate and lipid metabolism is carried out at the cellular level by the concentrations of the corresponding substrates and enzymes, as well as the degree of accumulation of the products of a particular reaction. These control mechanisms belong to the mechanisms of self-regulation and are implemented in both unicellular and multicellular organisms.
In the latter, regulation of the utilization of carbohydrates and fats can occur at the level of intercellular interactions. In particular, both types of metabolism are reciprocally mutually controlled: NEFA in muscles inhibit the breakdown of glucose, while glucose breakdown products in adipose tissue inhibit the formation of NEFA. In the most highly organized animals, a special intercellular mechanism for regulating interstitial metabolism appears, determined by the emergence in the process of evolution of the endocrine system, which is of paramount importance in the control of metabolic processes of the whole organism.
Among the hormones involved in the regulation of fat and carbohydrate metabolism in vertebrates, the central place is occupied by the following: hormones of the gastrointestinal tract, which control the digestion of food and the absorption of digestive products into the blood; insulin and glucagon are specific regulators of interstitial metabolism of carbohydrates and lipids; STH and functionally related “somatomedins” and SIF, glucocorticoids, ACTH and adrenaline are factors of nonspecific adaptation. It should be noted that many of these hormones are also directly involved in the regulation of protein metabolism (see Chapter 9). The rate of secretion of these hormones and the implementation of their effects on tissue are interrelated.
We cannot dwell specifically on the functioning of the hormonal factors of the gastrointestinal tract secreted during the neurohumoral phase of juice secretion. Their main effects are well known from the course of general physiology of humans and animals and, in addition, they have already been mentioned quite fully in Chapter. 3. Let us dwell in more detail on the endocrine regulation of interstitial metabolism of carbohydrates and fats.
Hormones and regulation of interstitial carbohydrate metabolism. An integral indicator of the balance of carbohydrate metabolism in the body of vertebrates is the concentration of glucose in the blood. This indicator is stable and is approximately 100 mg% (5 mmol/l) in mammals. Its normal deviations usually do not exceed ±30%. The level of glucose in the blood depends, on the one hand, on the influx of monosaccharide into the blood mainly from the intestines, liver and kidneys and, on the other hand, on its outflow into working and storage tissues (Fig. 95).
Rice. 95. Ways to maintain a dynamic balance of glucose in the blood
The membranes of muscle and adylose cells have a “barrier” to glucose transport; Gl-6-ph - glucose-6-phosphate
The influx of glucose from the liver and kidneys is determined by the ratio of the activities of glycogen phosphorylase and glycogen synthetase reactions in the liver, the ratio of the intensity of glucose breakdown and the intensity of gluconeogenesis in the liver and partly in the kidney. The entry of glucose into the blood directly correlates with the levels of the phosphorylase reaction and gluconeogenesis processes.
The outflow of glucose from the blood into tissues is directly dependent on the rate of its transport into muscle, adipose and lymphoid cells, the membranes of which create a barrier to the penetration of glucose into them (remember that the membranes of liver, brain and kidney cells are easily permeable to monosaccharide); metabolic utilization of glucose, in turn dependent on the permeability of membranes to it and on the activity of key enzymes of its breakdown; conversion of glucose into glycogen in liver cells (Levin et al., 1955; Newsholme and Randle, 1964; Foa, 1972).
All these processes associated with the transport and metabolism of glucose are directly controlled by a complex of hormonal factors.
Hormonal regulators of carbohydrate metabolism can be conditionally divided into two types based on their effect on the general direction of metabolism and the level of glycemia. The first type of hormones stimulates the utilization of glucose by tissues and its storage in the form of glycogen, but inhibits gluconeogenesis, and, therefore, causes a decrease in the concentration of glucose in the blood.
The hormone of this type of action is insulin. The second type of hormones stimulates the breakdown of glycogen and gluconeogenesis, and therefore causes an increase in blood glucose levels. Hormones of this type include glucagon (as well as secretin and VIP) and adrenaline. Hormones of the third type stimulate gluconeogenesis in the liver, inhibit the utilization of glucose by various cells and, although they enhance the formation of glycogen by hepatocytes, as a result of the predominance of the first two effects, as a rule, they also increase the level of glucose in the blood. Hormones of this type include glucocorticoids and growth hormone - “somatomedins”. At the same time, having a unidirectional effect on the processes of gluconeogenesis, glycogen synthesis and glycolysis, glucocorticoids and growth hormone - “somatomedins” have different effects on the permeability of the membranes of muscle and adipose tissue cells to glucose.
In terms of the direction of action on the concentration of glucose in the blood, insulin is a hypoglycemic hormone (hormone of “rest and saturation”), while hormones of the second and third types are hyperglycemic (hormones of “stress and starvation”) (Fig. 96).
Figure 96. Hormonal regulation of carbohydrate homeostasis:
solid arrows indicate stimulation of the effect, dotted arrows indicate inhibition
Insulin can be called a hormone for the absorption and storage of carbohydrates. One of the reasons for increased glucose utilization in tissues is stimulation of glycolysis. It is carried out, possibly, at the level of activation of the key enzymes of glycolysis, hexokinase, especially one of its four known isoforms - hexokinase II, and glucokinase (Weber, 1966; Ilyin, 1966, 1968). Apparently, the acceleration of the pentose phosphate pathway at the stage of the glucose-6-phosphate dehydrogenase reaction also plays a certain role in the stimulation of glucose catabolism by insulin (Leites and Lapteva, 1967). It is believed that in stimulating the uptake of glucose by the liver during dietary hyperglycemia under the influence of insulin, the most important role is played by the hormonal induction of the specific liver enzyme glucokinase, which selectively phosphorylates glucose at high concentrations.
The main reason for stimulating glucose utilization by muscle and fat cells is primarily a selective increase in the permeability of cell membranes to the monosaccharide (Lunsgaard, 1939; Levin, 1950). In this way, an increase in the concentration of substrates for the hexokinase reaction and the pentose phosphate pathway is achieved.
Increased glycolysis under the influence of insulin in skeletal muscles and myocardium plays a significant role in the accumulation of ATP and ensuring the performance of muscle cells. In the liver, increased glycolysis is apparently important not so much for increasing the inclusion of pyruvate in the tissue respiration system, but for the accumulation of acetyl-CoA and malonyl-CoA as precursors for the formation of polyhydric fatty acids, and therefore triglycerides (Newsholme, Start, 1973) .
Glycerophosphate formed during glycolysis is also included in the synthesis of neutral fat. In addition, in the liver, and especially in adipose tissue, to increase the level of lipogenesis from glucose, hormone stimulation of the glucose-6-phosphate dehydrogenase reaction plays a significant role, leading to the formation of NADPH, a reducing cofactor necessary for the biosynthesis of fatty acids and glycerophosphate. Moreover, in mammals, only 3-5% of absorbed glucose is converted into hepatic glycogen, and more than 30% is accumulated as fat, deposited in storage organs.
Thus, the main direction of action of insulin on glycolysis and the pentose phosphate pathway in the liver and especially in fatty tissue is to ensure the formation of triglycerides. In mammals and birds in adipocytes, and in lower vertebrates in hepatocytes, glucose is one of the main sources of stored triglycerides. In these cases, the physiological meaning of hormonal stimulation of carbohydrate utilization is largely reduced to stimulation of lipid deposition. At the same time, insulin directly affects the synthesis of glycogen - the stored form of carbohydrates - not only in the liver, but also in muscles, kidneys, and, possibly, adipose tissue.
The hormone has a stimulating effect on glycogen formation, increasing the activity of glycogen synthetase (transition of the inactive D-form to the active I-form) and inhibiting glycogen phosphorylase (transition of the low-active 6-form to the L-form) and thereby inhibiting glycogenolysis in cells (Fig. 97). Both effects of insulin on these enzymes in the liver are mediated, apparently, by activation of membrane proteinase, accumulation of glycopeptides, and activation of cAMP phosphodiesterase.
Figure 97. The main stages of glycolysis, gluconeogenesis and glycogen synthesis (according to Ilyin, 1965 with modifications)
Another important direction of the action of insulin on carbohydrate metabolism is the inhibition of the processes of gluconeogenesis in the liver (Krebs, 1964; Ilyin, 1965; Ixton et al., 1971). Inhibition of gluconeogenesis by the hormone occurs at the level of reducing the synthesis of the key enzymes phosphoenolpyruvate carboxykinase and fructose-16-biphosphatase. These effects are also mediated by an increase in the rate of formation of glycopeptides - hormone mediators (Fig. 98).
Glucose under any physiological conditions is the main source of nutrition for nerve cells. With an increase in insulin secretion, there is a slight increase in glucose consumption by nervous tissue, apparently due to the stimulation of glycolysis in it. However, at high concentrations of the hormone in the blood, causing hypoglycemia, carbohydrate starvation of the brain occurs and inhibition of its functions.
After the administration of very large doses of insulin, profound inhibition of the brain centers can lead first to the development of seizures, then to loss of consciousness and a drop in blood pressure. This condition, which occurs when the blood glucose concentration is below 45-50 mg%, is called insulin (hypoglycemic) shock. The convulsive and shock response to insulin is used for the biological standardization of insulin preparations (Smith, 1950; Stewart, 1960).
Regulation of carbohydrate metabolism is carried out at all stages by the nervous system and hormones. In addition, activity enzymes Some pathways of carbohydrate metabolism are regulated according to the “feedback” principle, which is based on the allosteric mechanism of interaction between the enzyme and the effector. Regulation of carbohydrate metabolism is carried out at all stages by the nervous system and hormones. In addition, activity enzymes Some pathways of carbohydrate metabolism are regulated according to the “feedback” principle, which is based on the allosteric mechanism of interaction between the enzyme and the effector. Allosteric effectors include the final reaction products, substrates, some metabolites, and adenyl mononucleotides. The most important role in focus carbohydrate metabolism (synthesis or breakdown of carbohydrates) is played by the ratio of coenzymes NAD + / NADH∙H + and the energy potential of the cell.
Constancy of blood glucose levels is the most important condition for maintaining normal functioning of the body. Normoglycemia is the result of the coordinated work of the nervous system, hormones and liver.
Liver- the only organ that stores glucose (in the form of glycogen) for the needs of the whole body. Thanks to active glucose-6-phosphate phosphatase, hepatocytes are able to form free glucose, which, unlike its phosphorylated forms, can penetrate through the cell membrane into the general circulation.
Of the hormones, the most prominent role is played by insulin. Insulin has its effect only on insulin-dependent tissues, primarily muscle and fat. The brain, lymphatic tissue, and red blood cells are insulin-independent. Unlike other organs, the action of insulin is not associated with the receptor mechanisms of its influence on the metabolism of hepatocytes. Although glucose freely penetrates into the liver cells, this is only possible if its concentration in the blood is increased. In hypoglycemia, on the other hand, the liver releases glucose into the blood (even despite high serum insulin levels).
The most significant effect of insulin on the body is a decrease in normal or elevated blood glucose levels - up to the development of hypoglycemic shock when high doses of insulin are administered. Blood glucose levels decrease as a result of: 1. Accelerates the entry of glucose into cells. 2. Increasing the use of glucose by cells.
Insulin accelerates the entry of monosaccharides into insulin-dependent tissues, especially glucose (as well as sugars of a similar configuration in the C 1 -C 3 position), but not fructose. The binding of insulin to its receptor on the plasma membrane leads to the movement of storage glucose transport proteins ( gluten 4) from intracellular depots and their inclusion in the membrane.
Insulin activates cells' use of glucose by:
activation and induction of the synthesis of key enzymes of glycolysis (glucokinase, phosphofructokinase, pyruvate kinase).
Increased incorporation of glucose into the pentose phosphate pathway (activation of glucose-6-phosphate and 6-phosphogluconate dehydrogenases).
Increasing glycogen synthesis by stimulating the formation of glucose-6-phosphate and activating glycogen synthase (at the same time, insulin inhibits glycogen phosphorylase).
Inhibition of the activity of key enzymes of gluconeogenesis (pyruvate carboxylase, phosphoenol-PVK-carboxykinase, biphosphatase, glucose-6-phosphatase) and repression of their synthesis (the fact of repression of the phosphoenol-PVK carboxykinase gene has been established).
Other hormones tend to increase blood glucose levels.
Glucagon and a adrenaline lead to an increase in glycemia by activating glycogenolysis in the liver (activation of glycogen phosphorylase), however, unlike adrenaline, glucagon does not affect glycogen phosphorylase muscles. In addition, glucagon activates gluconeogenesis in the liver, which also results in an increase in blood glucose concentrations.
Glucocorticoids help increase blood glucose levels by stimulating gluconeogenesis (by accelerating the catabolism of proteins in muscle and lymphoid tissues, these hormones increase the content of amino acids in the blood, which, when entering the liver, become substrates for gluconeogenesis). In addition, glucocorticoids prevent the body's cells from using glucose.
A growth hormone causes an increase in glycemia indirectly: by stimulating the breakdown of lipids, it leads to an increase in the level of fatty acids in the blood and cells, thereby reducing the latter’s need for glucose ( fatty acids are inhibitors of glucose use by cells).
Thyroxine, especially produced in excess quantities during hyperthyroidism, also contributes to an increase in blood glucose levels (due to increased glycogenolysis).
With normal glucose levels In the blood, the kidneys completely reabsorb it and sugar in the urine is not detected. However, if glycemia exceeds 9-10 mmol/l ( renal threshold ), then appears glucosuria . With some kidney lesions, glucose can be found in the urine even in normoglycemia.
Tests the body's ability to regulate blood glucose levels ( glucose tolerance ) is used to diagnose diabetes mellitus when administered orally glucose tolerance test:
The first blood sample is taken on an empty stomach after an overnight fast. Then the patient for 5 minutes. give a glucose solution to drink (75 g of glucose dissolved in 300 ml of water). After that every 30 minutes. blood glucose levels are determined over a 2-hour period
Rice. 10 “Sugar curve” in normal and pathological conditions
Ministry of Health of the Republic of Belarus
Educational institution
"Gomel State Medical University"
Department of Biological Chemistry
Discussed at a meeting of the department (MK or TsUNMS)____________________
Protocol No. _______
In biological chemistry
for 2nd year students of the Faculty of Medicine
Topic: Carbohydrates 4. Pathology of carbohydrate metabolism
Time__90 min___________________________
Learning objective:
1. Form ideas about the molecular mechanisms of the main disorders of carbohydrate metabolism.
LITERATURE
1. Human biochemistry: R. Murray, D. Grenner, P. Mayes, V. Rodwell. - M. book, 2004. - vol. 1. p. 205-211., 212-224.
2. Fundamentals of biochemistry: A. White, F. Hendler, E. Smith, R. Hill, I. Lehman.-M. book,
1981, vol. -.2,.s. 639-641,
3. Visual biochemistry: Kolman., Rem K.-G-M.book 2004.
4.Biochemical foundations...under. ed. corresponding member RAS E.S. Severina. M. Medicine, 2000.-p.179-205.
MATERIAL SUPPORT
1.Multimedia presentation
CALCULATION OF STUDY TIME
Total: 90 min
Introduction. The task of regulating and limiting carbohydrate consumption arises with particular urgency in connection with the prevention and treatment of diabetes, as well as identifying the correlation between excessive carbohydrate consumption with the incidence of certain diseases - “companions of obesity”, as well as with the development of atherosclerosis.
Define the concept of stress, list the phases of stress.
Explain why stress is called "general adaptation syndrome"
Name the stress-releasing hormonal systems.
List the most important hormones involved in the development of general adaptation syndrome.
List the main effects of hormones that provide short-term adaptation, explain the mechanism.
Explain the concept of “systemic structural trace of adaptation”, what is its physiological role?
The effects of which hormone ensure long-term adaptation; what are the mechanisms of action of this hormone?
List the hormones of the adrenal cortex.
Indicate the effect of glucocorticoids
for protein metabolism
for fat metabolism
for carbohydrate metabolism
Hormones in the regulation of the main parameters of homeostasis Hormonal regulation of metabolism
When we talk about the regulation of all types of metabolism, we are a little disingenuous. The fact is that an excess of fats will lead to disruption of their metabolism and the formation, for example, of atherosclerotic plaques, and a deficiency will lead to disruption of hormone synthesis only after a long time. The same applies to protein metabolism disorders. Only the level of glucose in the blood is the homeostatic parameter, a decrease in the level of which will lead to a hypoglycemic coma in a few minutes. This will happen primarily because the neurons will not receive glucose. Therefore, speaking about metabolism, we will first of all pay attention to the hormonal regulation of blood glucose levels, and at the same time we will dwell on the role of these same hormones in the regulation of fat and protein metabolism.
Regulation of carbohydrate metabolism
Glucose, along with fats and proteins, is a source of energy in the body. The body's energy reserves in the form of glycogen (carbohydrates) are small compared to the energy reserves in the form of fats. Thus, the amount of glycogen in the body of a person weighing 70 kg is 480 g (400 g - muscle glycogen and 80 g - liver glycogen), which is equivalent to 1920 kcal (320 kcal - liver glycogen and 1600 - muscle glycogen). The amount of circulating glucose in the blood is only 20 g (80 kcal). Glucose contained in these two depots is the main and almost the only source of nutrition for insulin-independent tissues. Thus, a brain weighing 1400 g with a blood supply intensity of 60 ml/100 g per minute consumes 80 mg/min of glucose, i.e. about 115 g in 24 hours. The liver is capable of generating glucose at a rate of 130 mg/min. Thus, more than 60% of the glucose produced in the liver goes to ensure the normal activity of the central nervous system, and this amount remains unchanged not only during hyperglycemia, but even during diabetic coma. CNS glucose consumption decreases only after its blood level drops below 1.65 mmol/L (30 mg%). From 2,000 to 20,000 glucose molecules are involved in the synthesis of one glycogen molecule. The formation of glycogen from glucose begins with the process of phosphorylation with the help of the enzymes glucokinase (in the liver) and hexokinase (in other tissues) with the formation of glucose-6-phosphate (G-6-P). The amount of glucose in the blood flowing from the liver depends mainly on two interrelated processes: glycolysis and gluconeogenesis, which in turn are regulated by the key enzymes phosphofructokinase and fructose-1, 6-bisphosphatase, respectively. The activity of these enzymes is regulated by hormones.
Regulation of blood glucose concentration occurs in two ways: 1) regulation based on the principle of parameter deviation from normal values. The normal blood glucose concentration is 3.6 – 6.9 mmol/l. The regulation of glucose concentration in the blood, depending on its concentration, is carried out by two hormones with opposite effects - insulin and glucagon; 2) regulation according to the principle of perturbation - this regulation does not depend on the concentration of glucose in the blood, but is carried out in accordance with the need to increase the level of glucose in the blood in various, usually stressful situations. Hormones that increase blood glucose levels are therefore called contrainsular. These include: glucagon, adrenaline, norepinephrine, cortisol, thyroid hormones, somatotropin, because the only hormone that reduces blood glucose levels is insulin (Figure 18).
The main place in the hormonal regulation of glucose homeostasis in the body is given to insulin. Under the influence of insulin, glucose phosphorylation enzymes are activated, catalyzing the formation of G-6-P. Insulin also increases the permeability of the cell membrane to glucose, which enhances its utilization. With an increase in the concentration of G-6-P in cells, the activity of processes for which it is the starting product (hexose monophosphate cycle and anaerobic glycolysis) increases. Insulin increases the share of glucose in the processes of energy formation while maintaining a constant overall level of energy production. Activation of glycogen synthetase and glycogen branching enzyme by insulin promotes increased glycogen synthesis. Along with this, insulin has an inhibitory effect on liver glucose-6-phosphatase and thus inhibits the release of free glucose into the blood. In addition, insulin inhibits the activity of enzymes that provide gluconeogenesis, thereby inhibiting the formation of glucose from amino acids. The end result of the action of insulin (if it is in excess) is hypoglycemia, which stimulates the secretion of contrainsular hormones that are insulin antagonists.
INSULIN- the hormone is synthesized by cells of the islets of Langerhans of the pancreas. The main stimulus for secretion is an increase in blood glucose levels. Hyperglycemia increases the production of insulin, hypoglycemia reduces the formation and flow of the hormone into the blood. In addition, insulin secretion increases under the influence. acetylcholine (parasympathetic stimulation), norepinephrine through -adrenergic receptors, and through -adrenergic receptors norepinephrine inhibits insulin secretion. Some gastrointestinal hormones, such as gastric inhibitory peptide, cholecystokinin, secretin, increase insulin output. The main effect of the hormone is to reduce blood glucose levels.
Under the influence of insulin, a decrease in the concentration of glucose in the blood plasma occurs (hypoglycemia). This is because insulin promotes the conversion of glucose into glycogen in the liver and muscles (glycogenesis). It activates enzymes involved in the conversion of glucose into liver glycogen and inhibits enzymes that break down glycogen.
Energy homeostasis provides the energy needs of tissues using various substrates. Because Carbohydrates are the main source of energy for many tissues and the only one for anaerobic tissues; regulation of carbohydrate metabolism is an important component of the body's energy homeostasis.
Regulation of carbohydrate metabolism is carried out at 3 levels:
central.
interorgan.
cellular (metabolic).
1. Central level of regulation of carbohydrate metabolism
The central level of regulation is carried out with the participation of the neuroendocrine system and regulates the homeostasis of glucose in the blood and the intensity of carbohydrate metabolism in tissues. The main hormones that maintain normal blood glucose levels of 3.3-5.5 mmol/l include insulin and glucagon. Glucose levels are also influenced by adaptation hormones - adrenaline, glucocorticoids and other hormones: thyroid, SDH, ACTH, etc.
2. Interorgan level of regulation of carbohydrate metabolism
Glucose-lactate cycle (Cori cycle) Glucose-alanine cycle
Glucose-lactate cycle does not require the presence of oxygen, always functions, ensures: 1) utilization of lactate formed under anaerobic conditions (skeletal muscles, red blood cells), which prevents lactic acidosis; 2) glucose synthesis (liver).
Glucose-alanine cycle functions in muscles during fasting. With glucose deficiency, ATP is synthesized due to the breakdown of proteins and the catabolism of amino acids under aerobic conditions, while the glucose-alanine cycle ensures: 1) removal of nitrogen from muscles in a non-toxic form; 2) glucose synthesis (liver).
3. Cellular (metabolic) level of regulation of carbohydrate metabolism
The metabolic level of regulation of carbohydrate metabolism is carried out with the participation of metabolites and maintains the homeostasis of carbohydrates within the cell. An excess of substrates stimulates their use, and products inhibit their formation. For example, excess glucose stimulates glycogenesis, lipogenesis and amino acid synthesis, while glucose deficiency stimulates gluconeogenesis. A deficiency of ATP stimulates glucose catabolism, and an excess, on the contrary, inhibits it.
IV. Pedagogical Faculty. Age characteristics of PFS and GNG, significance.
STATE MEDICAL ACADEMY
Department of Biochemistry
I approve
Head department prof., doctor of medical sciences
Meshchaninov V.N.
_____‘’_____________2005
LECTURE No. 10
Topic: Structure and metabolism of insulin, its receptors, glucose transport.
Mechanism of action and metabolic effects of insulin.
Faculties: therapeutic and preventive, medical and preventive, pediatric. 2nd course.
Pancreatic hormones
The pancreas performs two important functions in the body: exocrine and endocrine. The exocrine function is performed by the acinar part of the pancreas; it synthesizes and secretes pancreatic juice. The endocrine function is performed by the cells of the islet apparatus of the pancreas, which secrete peptide hormones involved in the regulation of many processes in the body. 1-2 million islets of Langerhans make up 1-2% of the mass of the pancreas.
In the islet part of the pancreas, there are 4 types of cells that secrete different hormones: A- (or α-) cells (25%) secrete glucagon, B- (or β-) cells (70%) - insulin, D- (or δ- ) cells (<5%) - соматостатин, F-клетки (следовые количества) секретируют панкреатический полипептид. Глюкагон и инсулин в основном влияют на углеводный обмен, соматостатин локально регулирует секрецию инсулина и глюкагона, панкреатический полипептид влияет на секрецию пищеварительных соков. Гормоны поджелудочной железы выделяются в панкреатическую вену, которая впадает в воротную. Это имеет большое значение т.к. печень является главной мишенью глюкагона и инсулина.
The structure of insulin
Insulin is a polypeptide consisting of two chains. Chain A contains 21 amino acid residues, chain B contains 30 amino acid residues. There are 3 disulfide bridges in insulin, 2 connect the A and B chains, 1 connects residues 6 and 11 in the A chain.
Insulin can exist in the form of: 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.
Insulins of some animals have significant similarity in primary structure to human insulin. Bovine insulin differs from human insulin by 3 amino acids, while porcine insulin differs by only 1 amino acid ( ala instead of tre at the C end of the B-chain).
In many positions of the A and B chain there are substitutions that do not affect the biological activity of the hormone. In the positions of disulfide bonds, hydrophobic amino acid residues in the C-terminal regions of the B-chain and the C- and N-terminal residues of the A-chain, substitutions are very rare, because These areas ensure the formation of the active center of insulin.
Insulin biosynthesis involves the formation of two inactive precursors, preproinsulin and proinsulin, which, as a result of sequential proteolysis, are converted into the active hormone.
1. Preproinsulin (L-B-C-A, 110 amino acids) is synthesized on ER ribosomes; its biosynthesis begins with the formation of the hydrophobic signal peptide L (24 amino acids), which directs the growing chain into the lumen of the ER.
2. In the ER lumen, preproinsulin is converted into proinsulin upon cleavage of the signal peptide by endopeptidase I. The cysteines in proinsulin are oxidized to form 3 disulfide bridges, proinsulin becomes “complex” and has 5% of the activity of insulin.
3. “Complex” proinsulin (B-C-A, 86 amino acids) enters the Golgi apparatus, where, under the action of endopeptidase II, it is cleaved to form insulin (B-A, 51 amino acids) and C-peptide (31 amino acids).
4. Insulin and C-peptide are incorporated into secretory granules, where insulin combines with zinc to form dimers and hexamers. In the secretory granule the content of insulin and C-peptide is 94%, proinsulin, intermediates and zinc - 6%.
5. Mature granules fuse with the plasma membrane, and insulin and C-peptide enter the extracellular fluid and then into the blood. In the blood, insulin oligomers break down. 40-50 units are secreted into the blood per day. insulin, this accounts for 20% of its total reserve in the pancreas. Insulin secretion is an energy-dependent process that occurs with the participation of the microtubular-villous system.
Scheme of insulin biosynthesis in β-cells of the islets of Langerhans
ER - endoplasmic reticulum. 1 - formation of a signal peptide; 2 - synthesis of preproinsulin; 3 - cleavage of signal peptide; 4 - transport of proinsulin to the Golgi apparatus; 5 - conversion of proinsulin into insulin and C-peptide and incorporation of insulin and C-peptide into secretory granules; 6 - secretion of insulin and C-peptide.
The insulin gene is located on chromosome 11. 3 mutations of this gene have been identified; carriers have low insulin activity, hyperinsulinemia, and no insulin resistance.
Regulation of insulin synthesis and secretion
Insulin synthesis is induced by glucose and insulin secretion. Represses the secretion of fatty acids.
Insulin secretion is stimulated by: 1. glucose (main regulator), amino acids (especially leu and arg); 2. Gastrointestinal hormones (β-adrenergic agonists, via cAMP): GUI , secretin, cholecystokinin, gastrin, enteroglucagon; 3. long-term high concentrations of growth hormone, cortisol, estrogens, progestins, placental lactogen, TSH, ACTH; 4. glucagon; 5. increase in K + or Ca 2+ in the blood; 6. drugs, sulfonylurea derivatives (glibenclamide).
Under the influence of somatostatin, insulin secretion decreases. β-cells are also influenced by the autonomic nervous system. The parasympathetic part (cholinergic endings of the vagus nerve) stimulates the release of insulin. The sympathetic part (adrenaline through α 2 -adrenergic receptors) suppresses the release of insulin.
Insulin secretion occurs with the participation of several systems, in which the main role belongs to Ca 2+ and cAMP.
Admission Sa 2+ into the cytoplasm is controlled by several mechanisms:
1). When the concentration of glucose in the blood increases above 6-9 mmol/l, it, with the participation of GLUT-1 and GLUT-2, enters β-cells and is phosphorylated by glucokinase. In this case, the concentration of glucose-6ph in the cell is directly proportional to the concentration of glucose in the blood. Glucose-6ph is oxidized to form ATP. ATP is also formed during the oxidation of amino acids and fatty acids. The more glucose, amino acids, and fatty acids there are in the β-cell, the more ATP is formed from them. ATP inhibits ATP-dependent potassium channels on the membrane, potassium accumulates in the cytoplasm and causes depolarization of the cell membrane, which stimulates the opening of voltage-dependent Ca 2+ channels and the entry of Ca 2+ into the cytoplasm.
2). Hormones that activate the inositol triphosphate system (TSH) release Ca 2+ from mitochondria and the ER.
cAMP is formed from ATP with the participation of AC, which is activated by the gastrointestinal hormones, TSH, ACTH, glucagon and Ca 2+ -calmodulin complex.
cAMP and Ca 2+ stimulate the polymerization of subunits into microtubules (microtubules). The effect of cAMP on the microtubular system is mediated through phosphorylation of PC A microtubular proteins. Microtubules are able to contract and relax, moving granules towards the plasma membrane allowing exocytosis.
Insulin secretion in response to glucose stimulation is a biphasic reaction consisting of a stage of rapid, early insulin release, called the first secretion phase (starts after 1 minute, lasts 5-10 minutes), and the second phase (lasts up to 25-30 minutes) .
Insulin transport. Insulin is water soluble and has no carrier protein in plasma. T1/2 of insulin in blood plasma is 3-10 minutes, C-peptide - about 30 minutes, proinsulin 20-23 minutes.
Insulin destruction occurs under the action of insulin-dependent proteinase and glutathione-insulin transhydrogenase in target tissues: mainly in the liver (about 50% of insulin is destroyed in 1 pass through the liver), to a lesser extent in the kidneys and placenta.