Insulin resistance in women and men

Insulin resistance syndrome is a condition when cells in the body become resistant to the effects of insulin, there is a violation of glucose uptake and assimilation. In most patients, the formation of the syndrome is due to poor nutrition, namely, excessive intake of carbohydrates and associated excessive insulin release.

The term "insulin resistance syndrome" was introduced into medicine about thirty years ago: it denotes a factor that causes a combination of metabolic disorders, including high blood pressure, diabetes, visceral obesity and hypertriglyceridemia. A similar term is "metabolic syndrome". [1]

Insulin resistance index: norm by age

The most accurate way to assess the presence or absence of insulin resistance is to perform an euglycemic hyperinsulinemic klemp. This test is recognized as indicative and can be used both in healthy people and in patients with diabetes mellitus. The disadvantages of this method are its complexity and costliness, so the test is used infrequently. Short variations of the intravenous and oral glucose tolerance test can be used.

The most common method of detecting insulin resistance is the determination of glucose and insulin levels on an empty stomach. High insulin levels against a background of normal glucose often indicate the presence of insulin resistance. In addition, various indices are used to determine this condition: they are calculated as a ratio of glucose and insulin levels on an empty stomach and after a meal - in particular, we are talking about the HOMA index. The higher the HOMA, the lower the insulin sensitivity and therefore the higher the insulin resistance. It is calculated according to the formula:

HOMA = (glucose value in mmol/liter - insulin value in µME/mL) : 22,5

The norm of the HOMA index should not exceed the value of 2.7. This figure is the same for both sexes, it does not depend on age in patients over 18 years of age. In adolescents, the index is slightly elevated, which is due to physiologic age-related insulin resistance.

It is also possible to define a caro index, which is defined as follows:

Caro = glucose in mmol/liter ׃ insulin in μME/mL

This index in the norm should not be less than 0.33. If it is lower, it indicates the presence of insulin resistance. [2]

Epidemiology

One of the most recognized global health problems is obesity, which has recently become widespread in many countries. Since 2000, the World Health Organization has elevated obesity to the rank of a non-communicable epidemic. According to statistics from 2015, the number of overweight people has more than doubled since 1985.

Specialists assume that in ten years the population of European countries will be overweight in more than 70% of men and 60% of women.

To date, there is repeated evidence of the relationship between obesity and the development of insulin resistance. Through research, scientists have proven that a 38% deviation of weight from the norm is associated with a 40% decrease in tissue sensitivity to insulin.

Almost all studies have confirmed that insulin resistance is more prevalent in women. The social level also plays a role.

In patients with a genetic predisposition, the debut of the disorder more often occurs against the background of progression of obesity (especially visceral obesity).

The prevalence of pathologic resistance in the world population is at least 10-15%. In people with impaired glucose tolerance this figure is much higher - 45-60%, and in patients with diabetes mellitus - about 80%.

Causes of the insulin resistance

Nowadays, diabetes mellitus and obesity have grown into a global problem. The pathologies occur equally often in children and adults. Due to excessive accumulation of fat against the background of a large intake of carbohydrates with food, insulin resistance with compensatory hyperinsulinemia develops, which becomes the basic prerequisite for the occurrence of type II diabetes mellitus.

In addition, insulin resistance is also one of the main components of the pathogenesis of such pathologies as cardiovascular diseases, non-alcoholic fatty liver disease, polycystic ovary syndrome (PCOS), gestational diabetes and so on. [3]

Loss of tissue sensitivity to the hormone insulin is sometimes a physiological response of the organism to some stressful influence. [4] But more often it is not physiology, but a pathological reaction. Here the "culprit" may be both external and internal factors. Genetic predisposition, development of subclinical inflammatory process of adipose tissue, imbalance of thyroid hormones, vitamin D and adipokines are not excluded. [5]

Risk factors

In insulin resistance, tissue sensitivity to the effects of insulin is reduced, especially in muscle, adipose tissue and the liver. As a consequence, glycogen production decreases, glycogenolysis and gluconeogenesis are activated.

In the evolutionary stream, in times of systematic alternation between periods of satiety and fasting, insulin resistance emerged as an adaptive response of the body. Today, this condition is found in one out of three practically healthy people. The pathology is provoked by the consumption of excessive amounts of caloric food, refined products, which is further aggravated by a sedentary lifestyle. [6]

Tissue insulin sensitivity is altered by many factors:

• periods of sexual development and pregnancy (hormonal surges);
• period of menopause and natural aging of the body;
• sleep quality;
• degree of physical activity.

However, most cases of insulin resistance are due to various diseases.

In addition to type II diabetes mellitus, which develops mainly with pre-existing insulin resistance, experts also identify other pathologies related to this condition. Among the endocrine disorders are female CJD and male erectile dysfunction, thyrotoxicosis and hypothyroidism, pheochromocytoma and acromegaly, Cushing's disease and decompensated type I diabetes.

Among non-endocrine pathologies it is important to mention hypertension, ischemic heart disease and heart failure, sepsis and renal failure, liver cirrhosis and oncology, rheumatoid arthritis and gout, various injuries, including burns. [7]

Additional risk factors:

• hereditary predisposition;
• obesity;
• diseases of the pancreas (pancreatitis, tumors) and other glands of internal secretion;
• viral diseases (chicken pox, rubella, epideparotitis, influenza, etc.);
• severe nervous stress, mental and emotional overstrain;
• advanced age.

Pathogenesis

The development of insulin resistance is based on receptor and postreceptor pathways of insulin impulse transportation. The passage of this impulse and the response to it are a complex combination of biochemical processes, each stage of which can be disturbed:

• mutations and inhibition of the tyrosine kinase action of the insulin receptor are possible;
• may be reduced and upregulation of phosphoinositide-3-kinase activity may be impaired;
• the incorporation of the GLUT4 transporter into cell membranes of insulin-sensitive tissues may be impaired.

Patterns of insulin resistance development vary from tissue to tissue. The decrease in the number of insulin receptors is noted mainly on adipocytes, while in myocytes it is not so noticeable. Insulinoreceptor tyrosine kinase activity is detected in both myocytes and adipose structures. Translocation disorders of intracellular glucose transporters to the plasma membrane are more intensely manifested in adipose cells.

A special role in the development of insulin resistance is played by changes in the sensitivity of muscle, liver and fat structures. Musculature reacts by increasing triglycerides and free fatty acid metabolism: as a result, glucose transportation and absorption are impaired in muscle cells. Since triglycerides are produced on the basis of free fatty acids, hypertriglyceridemia occurs. An increase in triglycerides aggravates insulin resistance, since triglycerides are non-hormonal insulin antagonists. As a result of the above processes, the function and abundance of GLUT4 glucose transporters is impaired. [8]

Insulin resistance of liver tissues is associated with the inability of insulin to inhibit gluconeogenesis, which leads to increased glucose production by hepatic cells. Due to the excess of free fatty acids, transportation and phosphorylation of glucose are inhibited and gluconeogenesis is activated. These reactions contribute to decreased insulin sensitivity.

In insulin resistance, the activity of lipoprotein lipase and triglyceridlipase in the liver changes, which leads to increased production and release of low-density lipoproteins, upsetting the processes of their elimination. The concentration of low-density lipoproteins increases, against the background of high content of free fatty acids in blood lipids accumulate in islets of Langerhans, lipotoxic effect on beta-cells occurs, which disturbs their functional state.

Insulin resistance in adipose tissue reveals itself by a decrease in the antilipotic capacity of insulin, which entails the accumulation of free fatty acids and glycerol. [9]

The inflammatory process in adipose tissue is of great importance in the formation of the pathological state. In obese patients, adipocytes hypertrophy, cell infiltration and fibrosis occur, the microcirculatory process changes, and the production of adipokines is disturbed. The level of nonspecific proinflammatory signaling cells such as C-reactive protein, leukocytes, fibrinogen increases in the blood. The adipose tissue produces cytokines and immunocomplexes that can initiate an inflammatory response. The expression of intracellular glucose transporters is blocked, resulting in impaired glucose utilization. [10]

Another pathogenetic mechanism may lie in inappropriate release of adipocytokines, including leptin, resistin, adiponectin, and so on. The role of hyperleptinemia is not excluded. It is known that there is a connection between leptin, adipocytes and pancreatic structures, which activates insulin production when insulin sensitivity is reduced.

Some role in the development of insulin resistance belongs to the lack of thyroid hormones, which is due to changes in insulin sensitivity of hepatic tissues. In this case, there is no inhibitory effect of insulin on the process of gluconeogenesis. The level of free fatty acids in the blood of patients with insufficient thyroid function has an additional effect. [11]

Other possible pathogenetic factors:

• vitamin D deficiency; [12]
• a breakdown in carbohydrate tolerance;
• the development of metabolic syndrome;
• the development of type II diabetes.

Insulin resistance and the ovaries

According to most physicians, polycystic ovarian syndrome and insulin resistance are linked by multiple pathogenetic processes. Polycystic ovary syndrome is a multifactorial heterogeneous pathology accompanied by failure of the monthly cycle, prolonged anovulation and hyperandrogenism, structural and dimensional changes of the ovaries.

Insulin resistance plays a special role in the formation of hyperandrogenism. The frequency of this phenomenon among women with diagnosed polycystic ovaries is estimated at 40-55% and more. Hyperinsulinemia increases the activation of cytochrome P450c17, which accelerates the production of androgens by Tec cells and ovarian stroma, favors the production of estrogens and luteinizing hormone. Against the background of increased insulin levels decreases the formation of globulins that bind sex hormones. This entails an increase in the content of free bioactive testosterone. Further increases the cellular sensitivity of granulosa to luteinizing hormone, which provokes small follicular luteinization. The growth of antral follicles stops, atresia occurs.

It was found that simultaneously with the stabilization of insulin levels, the concentration of androgens in the ovaries decreases and the ovulatory monthly cycle is restored.

Carbohydrate metabolism disorders are much more common in polycystic ovarian syndrome than in women with a healthy functioning reproductive system. Patients between 18 and 45 years of age with type II diabetes mellitus are more than one and a half times more likely to have polycystic ovaries than women without diabetes. During pregnancy, women with polycystic ovary syndrome and insulin resistance have a significantly increased risk of developing gestational diabetes mellitus.

Insulin resistance and diabetes mellitus

Diabetes mellitus is an urgent medical problem for the whole world, which is associated with a constant increase in incidence, increased incidence and high risk of complications, as well as difficulties in the therapeutic plan. The basic pathogenetic mechanism of formation of type II diabetes directly includes insulin resistance. The causes of its appearance may be different, but it is always about the presence of two components: genetic and acquired factors. For example, there are many cases of increased risk of insulin resistance in the first bloodline. Another key trigger factor is obesity, which with further progression aggravates the pathological condition. [13] Thus, one of the most frequent and early complications of diabetes is diabetic neuropathy, the severity of which depends on the insulin indicator, the degree of insulin resistance and endothelial dysfunction.

Insulin resistance influences the development of metabolic and cardiovascular disorders in patients with type II diabetes, which is associated with effects on cardiac muscle structure and function, blood pressure indices, as manifested by combined cardiovascular risk. [14]

Insulin resistance and papillomas

Experts point out some indirect, warning signs of insulin resistance, or prediabetes. One such sign is papillomas or warts that are found on the neck, armpits, groin, and chest. The papillomas themselves are harmless, but if they begin to appear abruptly and constantly, it indicates the presence of health problems - for example, hyperinsulinemia - an indicator of diabetes mellitus.

Papillomas are small skin growths that protrude above the surface. These growths are benign unless they are exposed to constant friction and sunlight.

With insulin resistance, the appearance of papillomas usually occurs against the background of other skin manifestations:

• itchy skin for no apparent reason;
• delayed wound healing;
• appearance of dark spots (more often in the area of natural skin folds);
• The appearance of reddish or yellowish spots.

In neglected cases, the skin changes, coarsens, turgor deteriorates, flaking, dandruff appears, and hair becomes dull. In such a situation, it is necessary to visit a doctor and carry out the necessary diagnostic measures.

Metabolic insulin resistance

One of the main components of metabolic insulin resistance is increased blood pressure, or hypertension. This is the most frequent vascular disorder. According to statistics, about 30-45% of patients who regularly experience hypertension simultaneously suffer from insulin resistance or glucose tolerance disorder. Insulin resistance gives rise to the development of tissue inflammation, "turns on" the renin-angiotensin-aldosterone mechanism, hyperactivates the sympathetic nervous system. Against the background of insulin resistance and increased insulin content in the blood, the endothelial response fades, which is associated with a decrease in nitric oxide activity, low formation of prostacyclin and increased production of vasoconstrictors.

The development of metabolic syndrome in adolescence is due to the formation of new functional links between endocrine and nervous mechanisms against the background of puberty. The level of sex hormones, growth hormone and cortisol increases. In such a situation, insulin resistance is physiological in nature and is transient. Only in some cases, the transformation of endocrine and neurovegetative processes and insufficient adaptation of metabolism lead to a failure of regulatory mechanisms, which entails the development of obesity with subsequent complications. At an early stage, there may be hyperactivity of the hypothalamic system and reticular formation, increased production of growth hormone, prolactin, adrenocorticotropic hormone, gonadotropins. As the condition worsens further, the function of the hypothalamic-pituitary mechanism is completely disrupted, the work of the hypophysis-hypothalamus-peripheral endocrine system ligament is disrupted.

Symptoms of the insulin resistance

The most common, but not the main sign of impending insulin resistance, is an increase in abdominal fat, where fat accumulates mainly in the abdominal and "flank" areas. The greatest danger is internal visceral obesity, in which fatty tissue accumulates around organs, preventing them from functioning properly. [15]

Abdominal fat, in turn, contributes to the development of other pathologic conditions. Among them:

• atherosclerosis;
• tumors, including malignant tumors;
• hypertension;
• joint pathologies;
• thrombosis;
• ovarian disorders in women.

Due to the fact that insulin resistance includes a number of pathological reactions and processes, in medicine they are combined into a syndrome called metabolic. Such a syndrome consists of the following manifestations:

• the formation of abdominal obesity;
• sustained increase in blood pressure over 140/90 mmHg;
• insulin resistance itself;
• Disorder of cholesterol metabolism, an increase in "bad" fractions and a decrease in "good" fractions.

In advanced cases, metabolic syndrome is complicated by heart attacks, strokes and so on. In order to prevent such complications, it is necessary to normalize body weight, regularly monitor blood pressure and blood sugar, as well as the levels of cholesterol fractions in the blood. [16]

First external signs

At the initial stage of development, insulin resistance does not manifest itself in any way: well-being practically does not suffer, there are no external signs. The first symptoms appear somewhat later:

The fat layer in the waist area increases (in men the waist volume begins to exceed 100-102 cm, and in women - more than 88-90 cm), gradually develops the so-called visceral, or abdominal obesity;

Skin problems appear: the skin becomes dry, dandruff and flaking are common, darkened spots may appear in areas of natural folds (armpits, neck, under the breasts, groin, etc.) and frequent friction (e.g., elbows) due to increased melanin production in response to excessive insulin activity;

Craving for sweets increases, a person can no longer tolerate long intervals between meals, there is a need to "constantly chew something", the feeling of satiety is lost even after a large meal.

If we consider changes in laboratory tests, then, first of all, we will talk about the increase in blood sugar and insulin levels on an empty stomach, as well as high cholesterol and uric acid.

Overweight is one of the main risk factors for carbohydrate metabolism disorders. Numerous scientific studies confirm that the risk of insulin resistance increases with the accumulation of fat mass in the body. It is also undeniable that the appearance of visceral (abdominal) obesity indicates an increased risk of dangerous cardiac and metabolic consequences. Therefore, both BMI calculation and waist circumference determination are necessary for risk assessment of patients.

The emergence of obesity and carbohydrate metabolism disorders is closely associated with the development of insulin resistance against the background of dysfunction and hypertrophy of adipocytes. A vicious circle emerges, provoking a full range of other pathological and physiological complications. In particular, the main signs of insulin resistance in overweight women are expressed, among others, in increased blood pressure, hyperlipidemia, atherosclerosis and so on. Such pathologies as diabetes mellitus, coronary heart disease, hypertension, fatty liver disease are also associated with excess weight. [17]

Signs of insulin resistance in normal-weight women are not as obvious as in obesity. It can be a disorder of the monthly cycle (including anovulation), hyperandrogenism, polycystic ovarian syndrome and, as a consequence, infertility. Hyperinsulinemia activates the production of ovarian androgens and depresses the release of globulins that bind sex hormones in the liver. This increases the circulation of free androgens in the circulatory system.

Although most patients with carbohydrate metabolism disorders are visibly obese, it is not uncommon to find insulin resistance in thin women. The idea is that many visibly thin people have large accumulations of visceral fat - deposits around internal organs. Such a problem is often not visible visually, it can only be detected by diagnostic tests. It turns out that, despite an adequate body mass index, these people have a significantly increased risk of developing not only metabolic disorders, but also diabetes mellitus and cardiovascular pathologies. Especially often excess visceral fat is found in thin women who maintain their weight solely by dieting, ignoring physical activity. According to research, only sufficient and regular physical activity prevents the formation of "internal" obesity. [18]

Psychosomatics of insulin resistance in women

Among the causes of insulin resistance, the involvement of genetic factors, viral infectious diseases and autoimmune mechanisms is most actively discussed. There is information about the influence of psychosocial factors on the stability of juvenile carbohydrate metabolism disorders.

The relationship between emotional overexcitation and endocrine response and stress reactions has been discovered. Feelings of fear and anger activate the adrenal cortex, as a result of which adrenaline stimulates the processes of carbohydrate metabolism: glucose release to maintain energy is increased.

Until about 50 years ago, it was suggested that emotional stress, fears, severe or prolonged anxiety, feelings of danger, and prolonged disagreement were involved in the increased secretion of catecholamines, increased blood glucose, and the appearance of glucosuria.

The predisposition to disorder is reinforced by the limitation of any of the regulatory mechanisms, the inability of the organism to overcome intense and prolonged stress. [19]

Insulin resistance and pregnancy

According to the results of numerous studies, it has been established that in pregnant women, especially in the second half of the gestation period, physiological insulin resistance occurs, which is of an adaptive nature, because it determines the energy restructuring in favor of active growth of the future child. The build-up of insulin resistance is usually associated with the influence of placental counterinsulatory hormones and decreased activity of glucose transporters. The development of compensatory hyperinsulinemia at first helps to maintain a normal state of carbohydrate metabolism. However, such physiological insulin resistance under the influence of external and internal factors can easily be transformed into pathological, which is associated with the loss of the ability of beta-cells to intensively secrete insulin.

Insulin resistance is of particular importance in the occurrence of pregnancy complications. The most common are gestational diabetes mellitus, gestational hypertension and pre-eclampsia, thromboembolism, fetal hypothermia, poor labor activity, and clinically narrow pelvis.

A relatively high HOMA at the onset of gestation is associated with a high risk of developing gestational diabetes. Such adverse events in overweight patients often lead to an involuntary cesarean section (risk increases approximately 2-fold).

Pathologic insulin resistance negatively affects the course of pregnancy in general. Significantly increases the risk of complications: threat of miscarriage in the I-II trimester, preeclampsia, chronic placental insufficiency. Also indicate a possible complicated course of the neonatal period in newborn babies: lesions of the central nervous system, asphyxia, edema, hypotrophy. The frequency of large fetuses is increasing.

Pathologic insulin resistance during pregnancy is talked about:

• if the HOMA-IR is greater than 2.21 +/- 0.64 in the second trimester;
• in the third trimester, the rate exceeds 2.84 +/- 0.99.

Insulin resistance in children

Insulin resistance and the associated metabolic syndrome are considered a precursor to type II diabetes mellitus. The incidence is increasing significantly in proportion to the growing population of obese children. [20]

Insulin resistance is inextricably linked to genetics, peculiarities of nutrition of the child, conducted medication, hormonal changes, lifestyle.

The risks of developing the disorder are increased in childhood:

• if you're overweight;
• if there is a direct hereditary predisposition, whether for diabetes, hypertension or atherosclerosis; [21]
• if the birth weight was over 4 kg.

Pediatric manifestations of insulin resistance are not always obvious. Sometimes children complain of constant fatigue, sudden feelings of hunger or thirst, visual disturbances, slow healing of abrasions and cuts. Most children with metabolic syndrome are passive, prone to depression. In the diet they give preference to carbohydrate food (unhealthy: sweets, fast food, etc.). Enuresis is possible in small children.

If there are suspicions of the development of such pathology, you should consult with a pediatric endocrinologist as soon as possible and take the necessary tests.

Forms

The sensitivity of tissues in the body to insulin is determined by various factors. These include a person's age and weight, physical condition and endurance, chronic diseases and bad habits, diet and lifestyle. [22]

Insulin resistance is found in type II diabetes mellitus, as well as in many other disorders and functional states, the appearance of which is based on metabolic disorders. Depending on this, endocrinologists divide such variants of pathology:

• physiological - it is a temporary adaptation mechanism that "turns on" during certain periods of change in energy intake and release - for example, during pregnancy or puberty, in old age, or against the background of improper nutrition;
• metabolic - develops simultaneously with dysmetabolic disorders - in particular, in type II diabetes, decompensated type I diabetes, diabetic ketoacidosis, prolonged starvation, obesity, alcohol intoxication;
• Endocrine insulin resistance - associated with diseases of the glands of internal secretion and is characteristic of thyrotoxicosis, hypothyroidism, Cushing's syndrome, pheochromocytoma, acromegaly;
• non-endocrine pathological - accompanies hypertension, chronic renal failure, liver cirrhosis, tumor cachexia, sepsis, burn disease, etc.

Complications and consequences

The most common consequences of insulin resistance are considered to be diabetes mellitus and cardiovascular pathologies. The fact is that the emergence of insulin resistance is closely related to the deterioration of the function of this hormone to cause vascular dilatation. And the loss of the ability of arterial vessels to dilate is the initial stage in the formation of circulatory disorders - angiopathies.

In addition, insulin resistance creates favorable conditions for the development of atherosclerosis, because it affects the activity of blood clotting factors and fibrinolysis processes. [23]

However, the most frequent complication of insulin resistance is considered to be type II diabetes mellitus. The cause of unfavorable outcome of events is prolonged compensation of hyperinsulinemia and further depletion of beta cells, reduction of insulin production and development of persistent hyperglycemia. [24]

Diagnostics of the insulin resistance

Detecting insulin resistance at an early stage is a rather difficult diagnostic task, which is due to the lack of a characteristic clinical picture that allows the patient to suspect the presence of the problem and seek medical help in a timely manner. In the vast majority of cases, the disorder is detected during endocrinologic examination for overweight or diabetes mellitus.

To assess the condition of the body and the need for treatment, the doctor may recommend taking these tests:

• general blood test - to exclude anemia and inflammatory diseases;
• general urinalysis - to assess kidney function, vulnerable in the development of diabetes mellitus;
• Biochemical blood test - to check the state of the liver and kidneys, to determine the quality of lipid metabolism.

Other possible tests include:

• Fasting blood glucose (at least 8 h of fasting);
• glucose tolerance test (venous blood is taken twice - on an empty stomach and after taking glucose diluted with water);
• glycated hemoglobin;
• Insulin, proinsulin, C-peptide, HOMA index, fructosamine.

What tests should I take for insulin resistance?

• Suppressive insulin test. Assessment of insulin resistance is based on prolonged glucose administration, with simultaneous inhibition of beta-cell response and endogenous glucose production. If the equilibrium glucose level is greater than or equal to 7.0, insulin resistance is considered confirmed.
• Oral glucose tolerance test. It involves measuring glucose, C-peptide, and insulin on an empty stomach and 2 hours after glucose consumption.
• Intravenous glucose tolerance test. It helps to determine the phasic insulin secretion during schematic administration of glucose and insulin. SI-4 min ˉ¹ SI-4 index is used to confirm insulin resistance.
• Insulin resistance index homa ir. The coefficient is calculated after a blood test: the values of insulin and plasma glucose levels on an empty stomach are taken into account. A high insulin resistance index - more than 2.7 - indicates the presence of a disorder.
• Caro index. Calculated by dividing the blood glucose concentration index by the insulin level index. In this case, a low insulin resistance index - less than 0.33 - indicates the presence of a disorder.

Instrumental diagnostics can be represented, first of all, ultrasound examination of the abdominal cavity. The method allows you to identify structural abnormalities in the pancreas, liver. This study is usually complex: at the same time it is possible to assess the state of the gallbladder, kidneys, spleen, in order to trace the development of associated pathologies.

It is also possible to prescribe other diagnostic measures - in particular, to identify complications of insulin resistance:

• scanning of renal vessels, brachiocephalic aortic branches, and lower extremity vessels;
• electrocardiography;
• Holter ECG monitoring;
• daily blood pressure monitoring;
• ophthalmoscopy;
• examination of the ocular fundus (Folk lens);
• ocular tonometry, visometry.

Differential diagnosis

Differential diagnosis is carried out with diabetes mellitus types I and II, with monogenic forms of diabetes. This is necessary to choose the right therapeutic approach. In addition, the correct diagnosis determines the prognosis of the course of the disorder, gives an idea of the possible risks of complications.

There is a special need for differential diagnosis in the following categories of patients:

• Children and adults who are overweight;
• Children with detected ketonuria or ketoacidosis;
• patients with an aggravated family history.

Differential diagnosis is performed in relation to the following pathologies:

• Type I diabetes mellitus with destructive changes in the beta cells of the pancreas with the development of complete insulin deficiency;
• Type II diabetes mellitus with predominant insulin resistance or impaired insulin secretion;
• with other diabetic variants (genetic functional disorders of beta cells, genetic disorders of insulin action, diseases of the exocrine part of the pancreas, endocrinopathies, drug-induced diabetes, infectious pathologies, immune-mediated diabetes);
• Gestational diabetes (occurs during pregnancy).

Treatment of the insulin resistance

Treatment for insulin resistance is not always necessary, as the condition may be physiologically normal at certain times in life - for example, physiologic insulin resistance occurs during puberty in adolescents and in women during pregnancy. This norm is the body's way of adapting to a possible prolonged period of fasting. [25]

As for insulin resistance as a pathology, the need for treatment is always present. If this is not done, the risks of developing serious diseases increase significantly.

How to reduce insulin resistance? First of all, it is necessary to normalize body weight. Against the background of decreasing fat layer gradually increases cellular sensitivity to insulin.

Weight loss can be achieved through two main means: regular exercise and dietary adjustments.

Physical activity should be regular, including mandatory aerobic exercise at least three times a week for 40-50 minutes. It is recommended to engage in swimming, light jogging, dancing, yoga, aerobics. Active training promotes intensive muscle work, and after all, there are many insulin receptors in muscle tissues, which become available for insulin.

A low-calorie diet with a drastic restriction or elimination of simple carbohydrates (sugar, cookies, candy, pastries) is another necessary step to overcome insulin resistance. If possible, snacks should be eliminated or made as healthy for the body as possible. Increasing the proportion of fiber in the diet and reducing animal fats by increasing vegetable oils is encouraged.

Many patients note that it is quite difficult to reduce weight with insulin resistance. In such a situation, if diet and sufficient physical activity do not lead to the expected result, the doctor prescribes drug treatment. Most often it includes taking Metformin - a drug that increases insulin sensitivity of tissues, reduces the accumulation of glucose (namely - glycogen in the muscles and liver), accelerating the absorption of glucose by muscle tissues and inhibiting its intestinal absorption. Metformin is taken only on prescription and under the supervision of the attending doctor, independent use of the drug is strictly prohibited, due to the high risk of side effects and a large list of contraindications.

Medications

As we have already mentioned, pathogenetic treatment of insulin resistance includes, first of all, a non-drug approach aimed at correcting weight and nutrition, avoiding bad habits and increasing physical activity - that is, leading a healthy lifestyle. Normalization of body weight and reduction of visceral fat is associated with optimization of tissue sensitivity to insulin and elimination of internal risk factors. According to studies, in people suffering from metabolic disorders, as weight normalized, the concentration of endothelin-1, a strong vasoconstrictor, decreased significantly. At the same time, levels of pro-inflammatory markers decreased. Patients whose body weight decreased by more than 10% significantly reduced the influence of factors in the development of cardiovascular pathologies.

In the absence of the expected effect on the background of non-medication methods (and not instead of them), drugs are prescribed. In most cases, such treatment includes the use of thiazolidinediones and biguanides.

The main and most popular drug of the biguanide series, Metformin, normalizes insulin sensitivity of hepatic tissues. This is manifested by a decrease in the reactions of glycogenolysis and gluconeogenesis in the liver. A somewhat smaller effect is observed in relation to muscle and fat tissues. According to the results of scientific studies, patients on the background of taking Metformin significantly reduced the risk of heart attack and stroke, and mortality decreased by more than 40%. Ten-year prognosis of the disease was also improved: weight normalization was noted, insulin resistance decreased, plasma triglycerides decreased, blood pressure stabilized. One of the common drugs containing Metformin is Glucofage: its initial dose is usually 500-850 mg 2-3 times a day with food. The maximum recommended dosage of the drug is 3000 mg per day, divided into three doses.

Another group of drugs are thiazolidinediones, or synthetic ligands of gamma receptors that are activated by peroxisome proliferator-activated receptors. Such receptors are mainly localized in the cell nuclei of muscle and adipose tissue; they are also present in myocardium, liver and kidney tissues. Thiazolidinediones are able to alter gene transcription in the regulation of glucose-fat metabolism. Glitazone is superior to Metformin in reducing insulin resistance in muscle and adipose tissues.

For patients with metabolic syndrome it is more appropriate to prescribe angiotensin-converting enzyme inhibitors. In addition to effective reduction of insulin resistance, such drugs have antihypertensive and antiatherosclerotic effect, do not disturb purine-lipid metabolism, have cardioprotective and nephroprotective ability.

Drugs that block angiotensin II receptors have similar hemodynamic and metabolic properties, inhibit sympathetic activity. In addition to lowering insulin resistance, there is an improvement in carbohydrate-fat and purine metabolism.

To date, the effectiveness of Moxonidine, a representative of a number of imidazoline receptor agonists, has been proven. This drug acts on receptors, stabilizes the activity of the sympathetic nervous system and inhibits the activity of the renin-angiotensin system, which entails a decrease in fat hydrolysis and the level of free fatty acids, reducing the number of insulin-resistant fibers in skeletal muscle, accelerating the transport and metabolism of glucose. As a result of these processes insulin sensitivity increases, triglycerides decrease, high-density lipoprotein content increases.

Other drugs that the doctor may prescribe are shown in the table.

Chromium active	A drug that reduces sugar addiction, eliminates constant cravings for sweets, helps to tolerate a low-carbohydrate diet more easily. Chromium active can be recommended as an additional remedy for insulin resistance and type II diabetes mellitus. Standard dosage of the drug: 1 tablet daily with food. Duration of the treatment course - 2-3 months.
Berberine	Plant alkaloid, effective in type II diabetes mellitus, hyperlipidemia and other metabolic disorders. Standardly take 1 capsule of Berberine up to three times a day with water. The duration of therapy is 2-4 weeks.
Inositol	A monovitamin that supports normal cell membrane function, regulates insulin activity and carbohydrate metabolism. Adult patients take 1 capsule daily or every other day.
Dietary supplements	Among other dietary supplements, the following products may be recommended: Diabetex Balance (Vitera); Vijaysar forte (Helaplant); Saccharonorm Doppelherz active; Glucokea (Prevent); Alphabet Diabetes.

Diet in insulin resistance

Carbohydrates are the main source of energy for the body. Over the years, people have consumed more and more carbohydrate foods, which are digested quickly and provide a lot of energy. Over time, this has led to the pancreas producing more insulin by which glucose can enter the cell to provide nourishment and energy. An overabundance of glucose leads to its deposition in fatty tissue and the liver (glycogen).

Insulin can be called a hormonal agent that "stores" fat because it activates the entry of glucose into fat structures and participates in the production of triglycerides and fatty acids and inhibits fat breakdown.

With excess insulin in the bloodstream, it is almost impossible to normalize body weight. However, the problem can be solved by a competent approach to changing the diet. You should not allow frequent snacking, because at every meal, even a small one, insulin is released. And its high level will be maintained by such snacks. To avoid this, nutritionists advise to switch to 3 meals a day with an interval between meals on average of 4 hours or even more - the quality of weight loss and correction of insulin resistance directly depends on it.

Most of the principles of the usual diet must be changed. It is important to take into account the glycemic index of the foods consumed: it is an indicator that shows the degree of increase in blood glucose levels after their consumption.

The glycemic index can be:

• low (less than 55);
• Medium (56 to 69);
• high (over 70).

Products with low and medium levels can be left in the diet, but those with high levels are categorically excluded from the menu. First of all, it is sugar and all sweets, pastry and white bread, fast food and snacks, sweet sodas and juices in packets. Fish, white meat, eggs, vegetables, herbs, berries, non-starchy fruits and root vegetables are left on the menu.

Foods that reduce insulin resistance

Dietary intake in insulin resistance is desirable to expand with the addition of such products:

• apples and pears;
• eggplant;
• peas and green peas;
• beans, including asparagus beans;
• apricots and peaches;
• cabbage (white cabbage, red cabbage, broccoli, Brussels sprouts, cauliflower);
• beets, carrots;
• 3% milk;
• cucumbers and tomatoes;
• lentils;
• berries (blackberries, raspberries, currants, mulberries);
• seeds, nuts (pumpkin seeds and sesame seeds, sunflower seeds, pine nuts, walnuts, peanuts, pistachios);
• wheat bran.

Adding seafood (oysters, crabs, sea fish, seaweed, shrimp) to the menu will positively affect the well-being of patients.

Moderately can be consumed buckwheat, oatmeal, pearl and barley groats.

Interval fasting

Dietary regimen and eating patterns are very important factors that directly affect insulin resistance. One such regimen that is very popular among people who want to lose weight is interval fasting. This is a specific dietary system where periods of eating alternate with certain periods of fasting, and there are practically no restrictions on food (only simple carbohydrates are excluded).

The essence of this regimen is the idea that in the process of evolution man was forced to go without food for several hours in a row, which contributed to the retention of normal weight and improved endurance and adaptation of the body. It should be noted that insulin resistance is often caused by the fact that people eat high-calorie meals without any restrictions on time and volume and do not move much, which causes glucose and insulin levels to rise, and obesity and other complications to develop.

Interval fasting can follow one of three basic variations:

1. Assumes 16-18 hours of fasting per day / 6-8 hours of allowed meals.
2. Assumes 12 h fasting / 12 hours of allowed food intake.
3. Assumes 14 hours of fasting / 10 hours of allowed meals.

Some patients also practice longer fasting for insulin resistance - for example, 24 to 72 hours. However, nutritionists state that such a dietary regimen can be dangerous to health, so they strongly discourage its widespread use.

In general, short interval fasting has a positive effect on insulin and glucose levels in people with insulin resistance. However, this method of dieting should be started only after prior consultation with physicians.

Vitamins for insulin resistance

Studies have shown that vitamin _B7 (biotin) directly affects glucose metabolism in the body. Biotin has the ability to lower blood sugar concentrations after consuming a carbohydrate meal. It also optimizes the insulin response to sugar load and reduces the degree of insulin resistance.

To date, the use of biotin is being actively studied. However, it is already reliably known that this vitamin significantly activates glucose metabolism in patients who are on dialysis, as well as in patients with diabetes mellitus.

Biotin is present in many foods - particularly liver, egg yolks, seeds and nuts, dairy products, avocados, etc. But this vitamin is water-soluble, so it does not accumulate in the body and must be supplied with food or with supplements that can be prescribed by a doctor.

Some nutritionists indicate that supplementation with tocopherol, a vitamin E supplement, is necessary. There is information that tocopherol significantly reduces the number of insulin receptors, reduces insulin resistance and improves glucose utilization in the body. Experts have ample evidence that vitamin E deficiency negatively affects metabolism and may worsen insulin resistance.

Carbohydrates in insulin resistance

Carbohydrates are one of the representatives of the triad of macronutrients that the body needs regularly and in sufficient quantities. Among the other macronutrients are the well-known fats and proteins. Carbohydrates primarily provide the body with energy: 1 g releases 4 calories. In the body, carbohydrates are broken down to glucose, which is the basic energy source for muscles and the brain.

Which foods are particularly rich in carbohydrates:

• baked goods and pasta;
• dairy products;
• candy;
• cereals, seeds, nuts;
• fruits, vegetables.

Carbohydrates can be represented by fiber, starch and sugar. The first two are complex, while sugar is a simple carbohydrate, especially easy to break down and digest. As a consequence, sugar increases blood glucose almost immediately, which is highly undesirable in insulin resistance.

Complex carbohydrates are broken down more slowly, so the glucose index increases gradually, while reducing the likelihood of forming fat deposits.

Complex carbohydrates are present in such foods:

• cereal;
• fruits and vegetables (apples, berries, carrots, cabbage, etc.);
• legumes.

For patients with insulin resistance, experts advise:

• give up sugar altogether;
• replace white flour and baked goods made from it with whole-grain analogs;
• add plant-based foods to your diet;
• Eat vegetable first courses daily, preferably with beans or lentils.

From sweets, pastries, packet juices, cookies and sweet sodas it is better to give up altogether.

The most useful carbohydrate is fiber: dietary fiber has a beneficial effect on the heart, helps maintain stable blood sugar levels. When soluble fiber passes through the small intestine, it binds to bile acids, which blocks their reabsorption. Cholesterol is used for further production of bile acids in the liver (unused cholesterol remains in the bloodstream, and it is known that its elevated level significantly increases the risk of cardiovascular pathologies). With the daily consumption of 10 g of fiber, the indicator of "bad" cholesterol decreases by 7%.

Alcohol in insulin resistance

The results of numerous studies have shown that the use of even small amounts of alcohol can complicate the course of insulin resistance, contribute to the development of ketoacidosis and angiopathies. In persons suffering from chronic alcoholism, in most cases there are pronounced metabolic disorders, liver function disorders, malfunctions in the pancreas. Against the background of alcohol abuse significantly increases the risk of complications.

At the initial stage, with regular alcohol intake, there is an increase in insulin production, a hypoglycemic state develops. Systematic alcohol intoxication leads to suppression of the secretory function of the pancreas.

Hyperglycemia is found in the first phase of alcohol withdrawal and hypoglycemia in the second and third phases.

Disorders of carbohydrate metabolism are often manifested by decreased fasting glucose values, basal hyperglycemia, and in many patients there is a dramatic decrease in glucose tolerance.

If the liver is affected, the breakdown of insulin is impaired and hypoglycemia is observed. If the pancreas is predominantly affected, insulin production is reduced, while the breakdown remains normal, resulting in hyperglycemia.

Alcohol abuse contributes to aggravation of dysproteinemia and increase of glycosylation index, inhibits microcirculatory processes in conjunctiva, impairs renal function.

Experts from the American Diabetes Association make the following recommendations for people with insulin resistance:

• should not consume more than 1 serving of alcohol per day for women and 2 servings for men (1 serving corresponds to 10 g of ethanol);
• should not be drunk on an empty stomach or with abnormal blood glucose levels;
• do not drink the entire portion in one gulp;
• it is important to drink enough regular drinking water at the same time;
• Instead of vodka, beer and champagne, it is better to choose natural dry or semi-dry wine;
• If it is not possible to give up drinking beer, you should choose the lightest and lightest variety.

If there are high risks of developing diabetes mellitus, it is better to give up alcohol completely.

Prevention

In order to prevent it, first of all, it is necessary to normalize body weight, daily exercise. During exercise, the muscles absorb almost 20 times more glucose than in a calm state. The most useful activities are considered swimming, cycling, intense walking. It is important to understand that physical activity does not necessarily have to be sports: an active walk, intensive cleaning of the apartment, and climbing to the upper floors without an elevator will do.

Another necessary preventive measure is proper nutrition. In the diet should reduce the amount of animal fats and sweets, exclude the use of alcoholic beverages. Danger is also hidden fats and carbohydrates, which are contained in sausages, semi-finished products, confectionery products of industrial production. The main dishes that should make up the daily menu are boiled, raw and baked vegetables, root vegetables, legumes, nuts. Very useful seafood, cereals, greens. The diet must necessarily include a sufficient amount of protein, including vegetable protein. It has been proven that the components of cinnamon can play an important role in alleviating and preventing signs and symptoms of metabolic syndrome, type 2 diabetes, as well as cardiovascular and related diseases. [26]

Easily digestible carbohydrates from the menu exclude: sugar, candy, cakes, ice cream, condensed milk, sweet sodas, jams and cookies - all these products significantly contribute to the development of insulin resistance.

Forecast

Insulin resistance can be corrected with a timely and comprehensive approach that includes diet and exercise regimen.

If you follow all the recommendations of doctors and nutritionists, the prognosis can be considered favorable. It is important both during active treatment and after its completion to control the intake of carbohydrates with food (especially pure sugar and sweets). It is necessary to avoid a passive lifestyle, practice regular exercise, do not allow the appearance of excess weight. If there is already any degree of obesity, it is necessary to direct all efforts to normalize weight.

In addition, even after successful treatment, insulin resistance should be monitored by periodically testing blood glucose, insulin, and cholesterol levels.