Insulin in Bodybuilding Note WP
Insulin in Bodybuilding | Note WP
Figure 61.3. Molecular mechanisms of insulin action. http://sportwiki.to
Insulin, From Wikipedia, the free encyclopedia
Insulin (from Latin insula – islet) is a protein-peptide hormone produced by the β-cells of the islets of Langerhans in the pancreas. Under physiological conditions in β-cells, insulin is formed from preproinsulin, a single-chain precursor protein, consisting of 110 amino acid residues. After transfer through the membrane of the rough endoplasmic reticulum, a signal peptide of 24 amino acids is cleaved from preproinsulin and proinsulin is formed. A long chain of proinsulin in the Golgi apparatus is packed into granules, where, as a result of hydrolysis, four basic amino acid residues are cleaved to form insulin and a C-terminal peptide (the physiological function of the C-peptide is unknown).
The insulin molecule consists of two polypeptide chains. One of them contains 21 amino acid residues (chain A), the second – 30 amino acid residues (chain B). The chains are connected by two disulfide bridges. The third disulfide bridge is formed within chain A. The total molecular weight of the insulin molecule is about 5700. The amino acid sequence of insulin is considered conserved. Most species have one insulin gene that codes for one protein. The exceptions are rats and mice (they each have two insulin genes), they produce two insulin, differing in two amino acid residues of the B-chain.
The primary structure of insulin in different biological species, incl. and in different mammals, is somewhat different. The closest to the structure of human insulin is porcine insulin, which differs from human insulin in one amino acid (it has an alanine residue in the B chain instead of the threonine amino acid residue). Bovine insulin differs from human insulin in three amino acid residues.
History reference. In 1921, Frederick G. Bunting and Charles G. Best, working in the laboratory of John J. R. McLeod at the University of Toronto, isolated an extract from the pancreas (later found to contain amorphous insulin), which lowered blood glucose levels in dogs with experimental diabetes mellitus. In 1922, a pancreatic extract was administered to the first patient, 14-year-old Leonard Thompson, with diabetes, and thereby saved his life. In 1923, James B. Collip developed a method for purifying the extract from the pancreas, which subsequently made it possible to obtain active extracts from the pancreas of pigs and cattle with reproducible results. In 1923 Bunting and McLeod were awarded the Nobel Prize in Physiology or Medicine for the discovery of insulin. In 1926 J. Abel and V. Du Vigneau obtained insulin in crystalline form. In 1939, insulin was first approved by the FDA (Food and Drug Administration). Frederick Sanger fully deciphered the amino acid sequence of insulin (1949–1954) In 1958, Sanger was awarded the Nobel Prize for his work on deciphering the structure of proteins, especially insulin. In 1963, artificial insulin was synthesized. The first recombinant human insulin was approved by the FDA in 1982. An ultra-short acting insulin analogue (insulin lispro) was approved by the FDA in 1996.
Mechanism of action. In realizing the effects of insulin, the leading role is played by its interaction with specific receptors localized on the plasma membrane of the cell, and the formation of the insulin-receptor complex. In combination with the insulin receptor, insulin enters the cell, where it affects the phosphorylation of cellular proteins and triggers numerous intracellular reactions.
In mammals, insulin receptors are found on almost all cells – both on classic insulin target cells (hepatocytes, myocytes, lipocytes), and on cells of blood, brain and gonads. The number of receptors on different cells ranges from 40 (erythrocytes) to 300 thousand (hepatocytes and lipocytes). The insulin receptor is constantly synthesized and degraded, with a half-life of 7-12 hours.
The insulin receptor is a large transmembrane glycoprotein consisting of two α-subunits with a molecular weight of 135 kDa (each containing 719 or 731 amino acid residues, depending on mRNA splicing) and two β-subunits with a molecular weight of 95 kDa (620 amino acid residues each). The subunits are interconnected by disulfide bonds and form a heterotetrameric β-α-α-β structure. The alpha subunits are located extracellularly and contain insulin-binding sites, being the recognition part of the receptor. The beta subunits form a transmembrane domain, possess tyrosine kinase activity and perform the function of signal conversion. The binding of insulin to the α-subunits of the insulin receptor leads to stimulation of the tyrosine kinase activity of β-subunits by autophosphorylation of their tyrosine residues, aggregation of α, β-heterodimers and rapid internalization of hormone-receptor complexes occurs. An activated insulin receptor triggers a cascade of biochemical reactions, incl. phosphorylation of other proteins inside the cell. The first of these reactions is the phosphorylation of four proteins called insulin receptor substrates, IRS-1, IRS-2, IRS-3, and IRS-4.
Pharmacological effects of insulin. Insulin affects almost all organs and tissues. However, its main targets are the liver, muscle and adipose tissue..
Endogenous insulin is the most important regulator of carbohydrate metabolism, exogenous insulin is a specific sugar-reducing agent. The effect of insulin on carbohydrate metabolism is due to the fact that it enhances the transport of glucose through the cell membrane and its utilization by tissues, promotes the conversion of glucose into glycogen in the liver. Insulin also inhibits endogenous glucose production by suppressing glycogenolysis (the breakdown of glycogen to glucose) and gluconeogenesis (synthesis of glucose from non-carbohydrate sources such as amino acids, fatty acids). In addition to hypoglycemic, insulin has a number of other effects.
The effect of insulin on fat metabolism is manifested in the inhibition of lipolysis, which leads to a decrease in the supply of free fatty acids into the bloodstream. Insulin interferes with the formation of ketone bodies in the body. Insulin enhances the synthesis of fatty acids and their subsequent esterification.
Insulin is involved in the metabolism of proteins: it increases the transport of amino acids across the cell membrane, stimulates the synthesis of peptides, reduces the consumption of protein by tissues, inhibits the conversion of amino acids into keto acids.
The action of insulin is accompanied by the activation or inhibition of a number of enzymes: glycogen synthetase, pyruvate dehydrogenase, hexokinase are stimulated, lipases are inhibited (both hydrolyzing lipids of adipose tissue, and lipoprotein lipase, which reduces the “clouding” of blood serum after ingestion of foods rich in fats).
In the physiological regulation of the biosynthesis and secretion of insulin by the pancreas, the main role is played by the concentration of glucose in the blood: with an increase in its content, insulin secretion increases, with a decrease, it slows down. In addition to glucose, insulin secretion is influenced by electrolytes (especially Ca2 + ions), amino acids (including leucine and arginine), glucagon, somatostatin.
Pharmacokinetics. Insulin preparations are administered subcutaneously, intramuscularly, or intravenously (intravenously, only short-acting insulins are administered and only with diabetic precoma and coma). You can not enter / in the suspension of insulin. The temperature of the insulin injected should be at room temperature, because cold insulin is absorbed more slowly. The most optimal way for continuous insulin therapy in clinical practice is subcutaneous administration.
The completeness of absorption and the onset of the effect of insulin depend on the injection site (usually insulin is injected into the abdomen, thighs, buttocks, upper arms), dose (volume of insulin injected), concentration of insulin in the preparation, etc..
The rate of absorption of insulin into the blood from the SC injection site depends on a number of factors – the type of insulin, the injection site, the local blood flow rate, local muscle activity, the amount of insulin injected (it is recommended to inject no more than 12-16 U of the drug per site). Insulin enters the bloodstream most rapidly from the subcutaneous tissue of the anterior abdominal wall, more slowly from the shoulder area, the front of the thigh, and even more slowly from the subscapularis and buttocks. This is due to the degree of vascularization of the subcutaneous fatty tissue of the listed areas. The insulin action profile is subject to significant fluctuations both among different people and among the same person..
In the blood, insulin binds to alpha and beta globulins, normally 5–25%, but the binding can increase during treatment due to the appearance of serum antibodies (the production of antibodies to exogenous insulin leads to insulin resistance; with the use of modern highly purified drugs, insulin resistance rarely occurs ). T1 / 2 from blood is less than 10 minutes. Most of the insulin that enters the bloodstream undergoes proteolytic degradation in the liver and kidneys. It is rapidly excreted from the body by the kidneys (60%) and the liver (40%); less than 1.5% is excreted in the urine unchanged.
Insulin preparations currently in use differ in a number of ways, incl. by source of origin, duration of action, pH of the solution (acidic and neutral), the presence of preservatives (phenol, cresol, phenol-cresol, methylparaben), insulin concentration – 40, 80, 100, 200, 500 U / ml.
Classification. Insulins are usually classified by origin (bovine, porcine, human, and human insulin analogs) and duration of action.
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Depending on the source of production, insulins of animal origin are distinguished (mainly preparations of porcine insulin), semi-synthetic human insulin preparations (obtained from porcine insulin by the method of enzymatic transformation), genetically engineered preparations of human insulin (DNA recombinant, obtained by genetic engineering).
For medical use, insulin was previously obtained mainly from the pancreas of cattle, then from the pancreas of pigs, given that porcine insulin is closer to human insulin. Since bovine insulin, which differs from human insulin in three amino acids, often causes allergic reactions, today it is practically not used. Pork insulin, which differs from human insulin in one amino acid, is less likely to cause allergic reactions. With insufficient purification, insulin drugs may contain impurities (proinsulin, glucagon, somatostatin, proteins, polypeptides) that can cause various side reactions. Modern technologies make it possible to obtain purified (mono-peak – chromatographically purified with the isolation of the “peak” of insulin), highly purified (mono-component) and crystallized insulin preparations. Among the preparations of insulin of animal origin, preference is given to monopic insulin obtained from the pancreas of pigs. Insulin obtained by genetic engineering methods fully corresponds to the amino acid composition of human insulin.
Insulin activity is determined by a biological method (by the ability to lower blood glucose in rabbits) or by a physicochemical method (by electrophoresis on paper or by chromatography on paper). One unit of action, or international unit, is the activity of 0.04082 mg of crystalline insulin. The human pancreas contains up to 8 mg of insulin (approximately 200 U).
According to the duration of action, insulin preparations are divided into short-acting and ultra-short-acting drugs – they imitate the normal physiological secretion of insulin by the pancreas in response to stimulation, medium-duration drugs and long-acting drugs – simulate the basal (background) insulin secretion, as well as combined drugs (combine both actions).
The following groups are testoheal distinguished:
Ultra-short-acting insulins (the hypoglycemic effect develops 10–20 minutes after SC administration, the peak of action is reached on average after 1–3 hours, the duration of action is 3–5 hours):
– insulin lispro (Humalog);
– insulin aspart (NovoRapid Penfill, NovoRapid FlexPen);
– insulin glulisine (Apidra).
Short-acting insulins (onset of action is usually 30-60 minutes; maximum action after 2-4 hours; duration of action up to 6-8 hours):
– soluble insulin [human genetic engineering] (Actrapid HM, Gensulin R, Rinsulin R, Humulin Regular);
– soluble insulin [human semi-synthetic] (Biogulin R, Humodar R);
– soluble insulin [porcine monocomponent] (Actrapid MS, Monodar, Monosuinsulin MK).
Sustained-release insulin preparations – includes medium-acting and long-acting drugs.
Insulins of medium duration of action (onset after 1.5-2 hours; peak after 3-12 hours; duration 8-12 hours):
– insulin isophane [human genetic engineering] (Biosulin N, Gansulin N, Gensulin N, Insuman Bazal GT, Insuran NPKh, Protafan NM, Rinsulin NPKh, Humulin NPKh);
– insulin isophane [human semi-synthetic] (Biogulin N, Humodar B);
– insulin isophane [pork monocomponent] (Monodar B, Protafan MS);
– compound insulin-zinc suspension (Monotard MS).
Long-acting insulins (onset after 4-8 hours; peak after 8-18 hours; total duration 20-30 hours):
– insulin glargine (Lantus);
– insulin detemir (Levemir Penfill, Levemir FlexPen).
Combined action insulin preparations (biphasic drugs) (the hypoglycemic effect begins 30 minutes after subcutaneous administration, reaches a maximum after 2-8 hours and lasts up to 18-20 hours):
– biphasic insulin [human semi-synthetic] (Biogulin 70/30, Humodar K25);
– biphasic insulin [human genetic engineering] (Gansulin 30R, Gensulin M 30, Insuman Comb 25 GT, Mikstard 30 NM, Humulin M3);
– biphasic insulin aspart (NovoMix 30 Penfill, NovoMix 30 FlexPen).
Ultrashort-acting insulins are analogs of human insulin. It is known that endogenous insulin in β-cells of the pancreas, as well as hormone molecules in produced short-acting insulin solutions, are polymerized and are hexamers. With subcutaneous administration, hexameric forms are absorbed slowly and the peak concentration of the hormone in the blood, similar to that in a healthy person after eating, cannot be created. The first short-acting analogue of insulin, which is absorbed from the subcutaneous tissue 3 times faster than human insulin, was insulin lispro. Insulin lispro is a human insulin derivative obtained by rearranging two amino acid residues in the insulin molecule (lysine and proline at positions 28 and 29 of the B chain). Modification of the insulin molecule disrupts the formation of hexamers and ensures a rapid flow of the drug into the blood. Almost immediately after subcutaneous administration in tissues, insulin lispro molecules in the form of hexamers rapidly dissociate into monomers and enter the bloodstream. Another insulin analogue, insulin aspart, was created by replacing proline at position B28 with negatively charged aspartic acid. Like insulin lispro, after s / c administration, it also rapidly decomposes into monomers. In insulin glulisine, the substitution of the amino acid asparagine of human insulin at position B3 for lysine and lysine at position B29 for glutamic acid also promotes faster absorption. Ultra-short-acting insulin analogs can be administered immediately before or after the best buy testosterone cream tablets for side effects meals.
Short-acting insulins (also called soluble insulins) are buffered solutions with neutral pH values (6.6-8.0). They are intended for subcutaneous, less often – intramuscular injection. If necessary, they are also administered intravenously. They have a fast and relatively short-term hypoglycemic effect. The effect after subcutaneous injection occurs within 15–20 minutes, reaches a maximum after 2 hours; the total duration of action is approximately 6 hours. They are used mainly in the hospital during the establishment of the required dose of insulin for the patient, and also when a quick (urgent) effect is required – in diabetic coma and precoma. With intravenous administration, T1 / 2 is 5 minutes, therefore, with diabetic ketoacidotic coma, insulin is administered intravenously by drip. Short-acting insulin preparations are also used as anabolic agents and are usually prescribed in small doses (4-8 IU 1-2 times a day).
Insulins of medium duration of action are less soluble, more slowly absorbed from the subcutaneous tissue, as a result of which they have a longer effect. The long-term effect of these drugs is achieved by the presence of a special prolongator – protamine (isophane, protaphan, basal) or zinc. The slowdown in the absorption of insulin in preparations containing insulin zinc compound suspension is due to the presence of zinc crystals. NPH-insulin (Hagedorn’s neutral protamine, or isophane) is a suspension of insulin and protamine (protamine, a protein isolated from fish milk) in a stoichiometric ratio.
Long-acting insulins include insulin glargine, an analogue of human insulin obtained by DNA recombinant technology, the first insulin preparation that does not have a pronounced peak of action. Insulin glargine is obtained by two modifications in the insulin molecule: replacement at position 21 of the A-chain (asparagine) with glycine and the addition of two arginine residues to the C-terminus of the B-chain. The drug is a clear solution with a pH of 4. The acidic pH stabilizes the insulin hexamers and ensures long-term and predictable absorption of the drug from the subcutaneous tissue. However, due to the acidic pH, insulin glargine cannot be combined with short-acting insulins, which have a neutral pH. A single dose of insulin glargine provides 24-hour peak-free glycemic control. Most insulin preparations have so-called. The “peak” of action, which is observed when the concentration of insulin in the blood reaches its maximum. Insulin glargine does not peak because it is released into the bloodstream at a relatively constant rate.
Long-acting insulin preparations are available in various dosage forms that have a hypoglycemic effect of varying duration (from 10 to 36 hours). The prolonged effect allows you to reduce the number of daily injections. They are usually produced in the form of suspensions administered only subcutaneously or intramuscularly. In diabetic coma and precomatous states, prolonged-release drugs are not used.
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Combined insulin preparations are suspensions consisting of short-acting neutral soluble insulin and insulin-isophane (intermediate duration) in certain proportions. This combination of insulins of different durations of action in one drug allows the patient to save the patient from two injections when using the drugs separately.
Indications. The main indication for the use of insulin is type 1 diabetes mellitus, but under certain conditions it is also prescribed for type 2 diabetes mellitus, incl. with resistance to oral hypoglycemic agents, with severe concomitant diseases, in preparation for surgical interventions, diabetic coma, with diabetes in pregnant women. Short-acting insulins are used not only in diabetes mellitus, but also in some other pathological processes, for example, with general depletion (as an anabolic agent), furunculosis, thyrotoxicosis, with stomach diseases (atony, gastroptosis), chronic hepatitis, initial forms of liver cirrhosis , as well as for some mental illnesses (the introduction of large doses of insulin – the so-called hypoglycemic coma); it is sometimes used as a component of “polarizing” solutions used to treat acute heart failure.
Insulin is the main specific treatment for diabetes mellitus. Treatment of diabetes mellitus is carried out according to specially developed schemes using insulin preparations of different duration of action. The choice of the drug depends on the severity and characteristics of the course of the disease, the general condition of the patient and on the speed of onset and duration of the drug’s hypoglycemic effect..
All insulin preparations are used subject to mandatory adherence to a dietary regimen with limited energy value of food (from 1700 to 3000 kcal).
When determining the dose of insulin, they are guided by the level of fasting glycemia and during the day, as well as by the level of glucosuria during the day. The final dose selection is carried out under the control of reducing hyperglycemia, glucosuria, as well as the general condition of the patient..
Contraindications. Insulin is contraindicated in diseases and conditions involving hypoglycemia (for example, insulinoma), in acute diseases of the liver, pancreas, kidneys, gastric and duodenal ulcers, decompensated heart defects, in acute coronary insufficiency and some other diseases..
Application during pregnancy. The main drug treatment for diabetes during pregnancy is insulin therapy, which is carried out under close supervision. In type 1 diabetes mellitus, insulin treatment is continued. With type 2 diabetes mellitus, oral hypoglycemic agents are canceled and diet therapy is performed.
Gestational diabetes mellitus (pregnancy diabetes) is a carbohydrate metabolic disorder that first occurs during pregnancy. Gestational diabetes mellitus is associated with an increased risk of perinatal mortality, the incidence of congenital malformations, and the risk of diabetes progression 5–10 years after delivery. Treatment for gestational diabetes begins with diet therapy. If diet therapy is ineffective, insulin is used.
For patients with pre-existing or gestational diabetes mellitus, it is important to maintain adequate metabolic regulation throughout pregnancy. The need for insulin may decrease in the first trimester of pregnancy and increase in the II – III trimesters. During and immediately after childbirth, the need for insulin can sharply decrease (the risk of hypoglycemia increases). Under these conditions, careful monitoring of blood glucose is essential..
Insulin does not cross the placental barrier. However, maternal IgG antibodies to insulin pass through the placenta and are likely to cause hyperglycemia in the fetus by neutralizing its secreted insulin. On the other hand, unwanted dissociation of insulin-antibody complexes can lead to hyperinsulinemia and hypoglycemia in the fetus or newborn. It has been shown that the transition from bovine / porcine insulin preparations to monocomponent preparations is accompanied by a decrease in the antibody titer. In this regard, during pregnancy, it is recommended to use only human insulin preparations..
Insulin analogs (like other recently developed drugs) are used with caution during pregnancy, although there is no reliable evidence of adverse effects. In accordance with the generally recognized recommendations of the FDA (Food and Drug Administration), which determine the possibility of using drugs during pregnancy, insulin preparations for the effect on the fetus are classified as category B (the study of reproduction in animals did not reveal an adverse effect on the fetus, but adequate and strictly controlled studies in pregnant women) women have not been carried out), or to category C (animal reproduction studies have revealed an adverse effect on the fetus, and adequate and strictly controlled studies in pregnant women have not been carried out, however, the potential benefits associated with the use of drugs in pregnant women may justify its use, despite possible risk). So, insulin lispro belongs to class B, and insulin aspart and insulin glargine – to class C.
Complications of insulin therapy. Hypoglycemia. The introduction of too high doses, as well as a lack of carbohydrate intake with food, can cause an undesirable hypoglycemic state, hypoglycemic coma with loss of consciousness, convulsions and inhibition of cardiac activity can develop. Hypoglycemia may also develop due to additional factors that increase insulin sensitivity (eg, adrenal insufficiency, hypopituitarism) or increase tissue glucose uptake (exercise).
Early symptoms of hypoglycemia, which are largely associated with the activation of the sympathetic nervous system (adrenergic symptoms), include tachycardia, cold sweat, tremors, with activation of the parasympathetic system – severe hunger, nausea, and a tingling sensation in the lips and tongue. At the first signs of hypoglycemia, urgent measures are necessary: the patient must drink sweet tea or eat a few lumps of sugar. In hypoglycemic coma, a 40% glucose solution is injected into a vein in an amount of 20–40 ml or more until the patient comes out of a coma (usually no more than 100 ml). You can also relieve hypoglycemia by intramuscular or subcutaneous administration of glucagon.
An increase in body weight during insulin therapy is associated with the elimination of glucosuria, an increase in the real caloric content of food, an increase in appetite and the stimulation of lipogenesis under the action of insulin. By following the principles of good nutrition, this side effect can be avoided..
The use of modern highly purified hormone preparations (especially genetically engineered preparations of human insulin) relatively rarely leads to the development of insulin resistance and allergy phenomena, but such cases are not excluded. The development of an acute allergic reaction requires immediate desensitizing therapy and drug replacement. If a reaction develops to bovine / porcine insulin preparations, they should be replaced with human insulin preparations. Local and systemic reactions (itching, local or systemic rash, the formation of subcutaneous nodules at the injection site) are associated with insufficient purification of insulin from impurities or with the use of bovine or porcine insulin that differs in amino acid sequence from human.
The most common allergic reactions are skin reactions mediated by IgE antibodies. Systemic allergic reactions, as well as insulin resistance mediated by IgG antibodies, are rarely observed.
Visual impairment. Transient refractive errors of the eye occur at the very beginning of insulin therapy and go away on their own after 2-3 weeks.
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Swelling. In the first weeks of therapy, transient edema of the legs also occurs due to fluid retention in the body, the so-called. insulin edema.
Local reactions include lipodystrophy at the site of repeated injections (a rare complication). Allocate lipoatrophy (the disappearance of subcutaneous fat deposits) and lipohypertrophy (an increase in subcutaneous fat deposits). These two states are of a different nature. Lipoatrophy, an immunological reaction mainly caused by the introduction of poorly purified preparations of insulin of animal origin, is practically not found at present. Lipohypertrophy also develops when highly purified preparations of human insulin are used and can occur when the injection technique is violated (cold preparation, alcohol getting under the skin), as well as due to the local anabolic action of the preparation itself. Lipohypertrophy creates a cosmetic defect that is a problem for patients. In addition, due to this defect, the absorption of the drug is impaired. To prevent the development of lipohypertrophy, it is recommended to constantly trenbolone acetate what is a tren ace change the injection sites within one area, leaving a distance between two punctures of at least 1 cm.
Local reactions such as pain at the injection site may occur.
Interaction. Insulin preparations can be combined with each other. Many drugs can cause hypo- or hyperglycemia, or alter the response of a patient with diabetes to treatment. Consideration should be given to the interaction possible with the simultaneous use of insulin with other drugs. Alpha-blockers and beta-adrenergic agonists increase the secretion of endogenous insulin and enhance the effect of the drug. The hypoglycemic effect of insulin is enhanced by oral hypoglycemic agents, salicylates, MAO inhibitors (including furazolidone, procarbazine, selegiline), ACE inhibitors, bromocriptine, octreotide, sulfonamides, anabolic steroids (especially oxandrolone, metrogens and tissue sensitivity increase tissue to glucagon, which leads to hypoglycemia, especially in the case of insulin resistance; a decrease in the dose of insulin may be necessary), somatostatin analogs, guanethidine, disopyramide, clofibrate, ketoconazole, lithium preparations, mebendazole, pentamidine, pyridoxine, propoxyphene, phenylbutoxinetazone, , lithium preparations, calcium preparations, tetracyclines. Chloroquine, quinidine, quinine reduce insulin degradation and may increase blood insulin concentration and increase the risk of hypoglycemia.
Carbonic anhydrase inhibitors (especially acetazolamide), by stimulating pancreatic β-cells, promote the release of insulin and increase the sensitivity of receptors and tissues to insulin; although the simultaneous use of these drugs with insulin may increase the hypoglycemic effect, the effect may be unpredictable.
A number of drugs cause hyperglycemia in healthy people and aggravate the course of the disease in patients with diabetes mellitus. The hypoglycemic effect of insulin is weakened by: antiretroviral drugs, asparaginase, oral hormonal contraceptives, glucocorticoids, diuretics (thiazide, ethacrynic acid), heparin, H2-receptor antagonists, sulfinpyrazone, tricyclic antidepressants, dobutamidamine, isotinazine CCB, diazoxide, morphine, phenytoin, growth hormone, thyroid hormones, phenothiazine derivatives, nicotine, ethanol.
Glucocorticoids and epinephrine have the opposite effect of insulin on peripheral tissues. Thus, long-term use of systemic glucocorticoids can cause hyperglycemia, up to diabetes mellitus (steroid diabetes), which can occur in about 14% of patients taking systemic corticosteroids for several weeks or with long-term use of topical corticosteroids. Some drugs inhibit insulin secretion directly (phenytoin, clonidine, diltiazem) or by reducing potassium stores (diuretics). Thyroid hormones speed up insulin metabolism.
Beta-blockers, oral hypoglycemic agents, glucocorticoids, ethanol, salicylates most significantly and often affect the action of insulin.
Ethanol inhibits gluconeogenesis in the liver. This effect is seen in all people. In this regard, it should be borne in mind that the abuse of alcoholic beverages against the background of insulin therapy can lead to the development of a severe hypoglycemic state. Small amounts of alcohol taken with food usually do not cause problems.
Beta-blockers can inhibit insulin secretion, alter carbohydrate metabolism, and increase peripheral insulin resistance, leading to hyperglycemia. However, they can also inhibit the effect of catecholamines on gluconeogenesis and glycogenolysis, which is associated with the risk of severe hypoglycemic reactions in patients with diabetes mellitus. Moreover, any of the beta-blockers can mask adrenergic symptoms caused by a decrease in blood glucose levels (including tremors, palpitations), thereby disrupting the patient’s timely recognition of hypoglycemia. Selective beta1-blockers (including acebutolol, atenolol, betaxolol, bisoprolol, metoprolol) exhibit these effects to a lesser extent.
NSAIDs and salicylates in high doses inhibit the synthesis of prostaglandin E (which inhibits the secretion of endogenous insulin) and thus increase the basal insulin secretion, increase the sensitivity of β-cells of the pancreas to glucose; hypoglycemic effect with simultaneous use may require dose adjustment of NSAIDs or salicylates and / or insulin, especially with long-term joint use.
Currently, a significant number of insulin preparations are produced, incl. obtained from the pancreas of animals and synthesized by genetic engineering. The drugs of choice for insulin therapy are genetically engineered highly purified human insulins with minimal antigenicity (immunogenic activity), as well as analogs of human insulin.
Insulin preparations are produced in glass vials, hermetically sealed with rubber stoppers with aluminum rolling, in special so-called. insulin syringes or syringe pens. When using syringe pens, the preparations are in special cartridge vials (penfill).
Intranasal insulin and oral insulin preparations are being developed. When insulin is combined with a detergent and is administered as an aerosol to the nasal mucosa, the effective plasma level is reached as quickly as with an iv bolus. Intranasal and oral insulin preparations are under development or in clinical trials.