Symptoms of diabetes mellitus

Symptoms of diabetes mellitus are manifested in two ways. This is due to acute or chronic insulin deficiency, which in turn can be absolute or relative. Acute insulin deficiency causes a state of decompensation of carbohydrate and other types of metabolism, accompanied by clinically significant hyperglycemia, glucosuria, polyuria, polydipsia, weight loss against the background of hyperphagia, ketoacidosis, up to diabetic coma. Chronic insulin deficiency against the background of subcompensated and periodically compensated course of diabetes mellitus is accompanied by clinical manifestations characterized as "late diabetic syndrome" (diabetic retinopathy, neuropathy and nephropathy), which is based on diabetic microangiopathy and metabolic disorders typical for the chronic course of the disease.

The mechanism of development of clinical manifestations of acute insulin deficiency includes disorders of carbohydrate, protein and fat metabolism, which cause hyperglycemia, hyperaminocidemia, hyperlipidemia and ketoacidosis. Insulin deficiency stimulates gluconeogenesis and glycogenolysis, and suppresses glycogenesis in the liver. Carbohydrates (glucose) coming with food are metabolized in the liver and insulin-dependent tissues to a lesser extent than in healthy individuals. Stimulation of glucogenesis by glucagon (with insulin deficiency) leads to the use of amino acids (alanine) for the synthesis of glucose in the liver. The source of amino acids is tissue protein, which is subject to increased decay. Since the amino acid alanine is used in the process of gluconeogenesis, the content of branched-chain amino acids (valine, leucine, isoleucine) in the blood increases, the utilization of which by muscle tissue for protein synthesis also decreases. Thus, hyperglycemia and aminocidemia occur in patients. Increased consumption of tissue protein and amino acids is accompanied by a negative nitrogen balance and is one of the reasons for weight loss in patients, and significant hyperglycemia - glucosuria and polyuria (as a result of osmotic diuresis). Fluid loss with urine, which can reach 3-6 l / day, causes intracellular dehydration and polydipsia. With a decrease in intravascular blood volume, arterial pressure decreases and the hematocrit number increases. Under conditions of insulin deficiency, the main energy substrates of muscle tissue are free fatty acids, which are formed in adipose tissue as a result of increased lipolysis - hydrolysis of triglycerides (TG). Its stimulation as a result of activation of hormone-sensitive lipase causes an increased flow of FFA and glycerol into the bloodstream and liver. The former, being oxidized in the liver, serve as a source of ketone bodies (beta-hydroxybutyric and acetoacetic acids, acetone), which accumulate in the blood (partially utilized by muscles and CNS cells), contributing to ketoacidosis, a decrease in pH and tissue hypoxia. Partially, FFA in the liver are used for the synthesis of TG, which cause fatty infiltration of the liver, and also enter the blood, which explains the hyperglyceridemia and increased FFA (hyperlipidemia) often observed in patients.

Progression and increase of ketoacidosis increase tissue dehydration, hypovolemia, hemoconcentration with a tendency to develop disseminated intravascular coagulation syndrome, deterioration of blood supply, hypoxia and edema of the cerebral cortex, and development of diabetic coma. A sharp decrease in renal blood flow can cause necrosis of the renal tubules and irreversible anuria.

The characteristics of the course of diabetes mellitus, as well as its clinical manifestations, largely depend on its type.

Type I diabetes usually manifests itself with pronounced clinical symptoms reflecting its characteristic insulin deficiency in the body. The onset of the disease is characterized by significant metabolic disorders causing clinical manifestations of diabetes decompensation (polydipsia, polyuria, weight loss, ketoacidosis), developing over several months or days. Often, the disease first manifests itself as diabetic coma or severe acidosis. After treatment, which in the vast majority of cases includes insulin therapy, and diabetes compensation, an improvement in the course of the disease is observed. Thus, in patients, even after a diabetic coma, the daily need for insulin gradually decreases, sometimes up to its complete cancellation. An increase in glucose tolerance, leading to the possibility of canceling insulin therapy after the elimination of pronounced metabolic disorders characteristic of the initial period of the disease, is observed in many patients. The literature describes fairly frequent cases of temporary recovery of such patients. However, after several months, and sometimes after 2-3 years, the disease recurred (especially against the background of a previous viral infection), and insulin therapy became necessary throughout life. This long-noted pattern in foreign literature has been called the "diabetic honeymoon", when there is remission of the disease and no need for insulin therapy. Its duration depends on two factors: the degree of damage to the beta cells of the pancreas and its ability to regenerate. Depending on the predominance of one of these factors, the disease can immediately take on the character of clinical diabetes or remission will occur. The duration of remission is additionally influenced by such external factors as the frequency and severity of concomitant viral infections. We observed patients in whom the duration of remission reached 2-3 years against the background of the absence of viral and intercurrent infections. At the same time, not only the glycemic profile, but also the glucose tolerance test (GTT) indicators in patients did not deviate from the norm. It should be noted that in a number of studies, cases of spontaneous remission of diabetes were assessed as a result of the therapeutic effect of sulfonamide hypoglycemic drugs or biguanides, while other authors attributed this effect to diet therapy.

After the development of persistent clinical diabetes, the disease is characterized by a small need for insulin, which increases and remains stable for 1-2 years. The clinical course subsequently depends on the residual secretion of insulin, which can vary significantly within the subnormal values of C-peptide. With very low residual secretion of endogenous insulin, a labile course of diabetes with a tendency to hypoglycemia and ketoacidosis is observed, due to the high dependence of metabolic processes on the administered insulin, the nature of nutrition, stress and other situations. Higher residual secretion of insulin ensures a more stable course of diabetes and a lower need for exogenous insulin (in the absence of insulin resistance).

Sometimes diabetes mellitus type I is combined with autoimmune endocrine and non-endocrine diseases, which is one of the manifestations of autoimmune polyendocrine syndrome. Since autoimmune polyendocrine syndrome can also include damage to the adrenal cortex, when blood pressure decreases, it is necessary to clarify their functional state in order to take adequate measures.

As the disease duration increases (after 10-20 years), clinical manifestations of late diabetic syndrome appear in the form of retinopathy and nephropathy, which progress more slowly with good compensation of diabetes mellitus. The main cause of death is renal failure and, much less frequently, complications of atherosclerosis.

According to the severity, type I diabetes is divided into moderate and severe forms. Moderate severity is characterized by the need for insulin replacement therapy (regardless of the dose) in the case of uncomplicated diabetes mellitus or the presence of retinopathy stages I and II, nephropathy stage I, peripheral neuropathy without severe pain syndrome and trophic ulcers. Severe severity includes insulin-deficiency diabetes in combination with retinopathy stages II and III or nephropathy stages II and III, peripheral neuropathy with severe pain syndrome or trophic ulcers, neurodystrophic blindness that is difficult to treat, encephalopathy, severe manifestations of autonomic neuropathy, a tendency to ketoacidosis, repeated comatose state, labile course of the disease. In the presence of the listed manifestations of microangiopathy, the need for insulin and the level of glycemia are not taken into account.

The clinical course of type II diabetes mellitus (insulin-independent) is characterized by its gradual onset, without signs of decompensation. Patients most often consult a dermatologist, gynecologist, neurologist about fungal diseases, furunculosis, epidermophytosis, vaginal itching, leg pain, periodontal disease, and visual impairment. During examination of such patients, diabetes mellitus is detected. Often, diabetes is first diagnosed during myocardial infarction or stroke. Sometimes the disease debuts with hyperosmolar coma. Due to the fact that the onset of the disease is unnoticeable in most patients, it is very difficult to determine its duration. This may explain the relatively rapid (after 5-8 years) appearance of clinical signs of retinopathy or its detection even during the primary diagnosis of diabetes mellitus. The course of diabetes type II is stable, without a tendency to ketoacidosis and hypoglycemic states against the background of diet alone or in combination with oral hypoglycemic drugs. Since diabetes of this type usually develops in patients over 40 years of age, it is often combined with atherosclerosis, which has a tendency to rapid progression due to the presence of risk factors in the form of hyperinsulinemia and hypertension. Complications of atherosclerosis are most often the cause of death in this category of patients with diabetes mellitus. Diabetic nephropathy develops much less frequently than in patients with type I diabetes.

Type II diabetes mellitus is divided into 3 forms according to its severity: mild, moderate and severe. The mild form is characterized by the possibility of compensating diabetes only with diet. It is likely to be combined with stage I retinopathy, stage I nephropathy, and transient neuropathy. Moderate diabetes is typically compensated with oral hypoglycemic drugs. It is possible to combine it with stage I and II retinopathy, stage I nephropathy, and transient neuropathy. In severe forms, compensation is achieved with hypoglycemic drugs or periodic insulin administration. At this stage, stage III retinopathy, stage II and III nephropathy, severe manifestations of peripheral or autonomic neuropathy, and encephalopathy are observed. Sometimes severe diabetes is diagnosed in patients compensated with diet, in the presence of the above manifestations of microangiopathy and neuropathy.

Diabetic neuropathy is a typical clinical manifestation of diabetes mellitus; it is observed in 12-70% of patients. Its frequency among patients increases significantly after 5 years or more of diabetes, regardless of its type. However, the correlation of neuropathy with the duration of diabetes is not absolute, so there is an opinion that the frequency of neuropathy is largely influenced by the nature of compensation of diabetes mellitus, regardless of its severity and duration. The absence of clear data in the literature on the prevalence of diabetic neuropathy is largely due to insufficient information on its subclinical manifestations. Diabetic neuropathy includes several clinical syndromes: radiculopathy, mononeuropathy, polyneuropathy, amyotrophy, vegetative (autonomous) neuropathy and encephalopathy.

Radiculopathy is a rather rare form of somatic peripheral neuropathy, which is characterized by acute shooting pains within one dermatome. The basis of this pathology is demyelination of the axial cylinders in the posterior roots and columns of the spinal cord, which is accompanied by a violation of deep muscle sensitivity, the disappearance of tendon reflexes, ataxia and instability in the Romberg pose. In some cases, the clinical picture of radiculopathy can be combined with uneven pupils, which is regarded as diabetic pseudotabes. Diabetic radiculopathy must be differentiated from osteochondrosis and deforming spondylosis of the spine.

Mononeuropathy is the result of damage to individual peripheral nerves, including cranial nerves. Spontaneous pain, paresis, sensory disturbances, decreased and lost tendon reflexes in the area of the affected nerve are characteristic. The pathological process can damage the nerve trunks of the III, V, VI-VIII pairs of cranial nerves. The III and VI pairs are affected significantly more often than others: approximately 1% of patients with diabetes mellitus experience paralysis of the extraocular muscles, which is combined with pain in the upper part of the head, diplopia and ptosis. Damage to the trigeminal nerve (V pair) manifests itself in attacks of intense pain in one half of the face. Pathology of the facial nerve (VII pair) is characterized by unilateral paresis of the facial muscles, and the VIII pair - by hearing loss. Mononeuropathy is detected both against the background of long-term diabetes mellitus and impaired glucose tolerance.

Polyneuropathy is the most common form of somatic peripheral diabetic neuropathy, which is characterized by distal, symmetrical and predominantly sensory disturbances. The latter are observed in the form of "socks and gloves syndrome", and this pathology manifests itself much earlier and more severely in the legs. Characteristically, there is a decrease in vibration, tactile, pain and temperature sensitivity, a decrease and loss of Achilles and knee reflexes. Damage to the upper limbs is less common and correlates with the duration of diabetes mellitus. Subjective sensations in the form of paresthesia and intense night pain may precede the appearance of objective signs of neurological disorders. Severe pain syndrome and hyperalgesia, increasing at night, cause insomnia, depression, loss of appetite, and in severe cases - a significant decrease in body weight. In 1974, M. Ellenberg described "diabetic polyneuropathic cachexia". This syndrome develops mainly in elderly men and is combined with intense pain, anorexia, and weight loss reaching 60% of total body weight. No correlation with the severity and type of diabetes has been noted. A similar case of the disease in an elderly woman with type II diabetes has been published in Russian literature. Distal polyneuropathy often causes trophic disorders in the form of hyperhidrosis or anhidrosis, thinning of the skin, hair loss, and much less often trophic ulcers, mainly on the feet (neurotrophic ulcers). Their characteristic feature is the preservation of arterial blood flow in the vessels of the lower extremities. Clinical manifestations of diabetic somatic distal neuropathy usually undergo regression under the influence of treatment within a period of several months to 1 year.

Neuroarthropathy is a rather rare complication of polyneuropathy and is characterized by progressive destruction of one or more joints of the foot ("diabetic foot"). This syndrome was first described in 1868 by the French neurologist Charcot in a patient with tertiary syphilis. This complication is observed in many conditions, but most often in patients with diabetes mellitus. The prevalence of neuropathy is approximately 1 case per 680-1000 patients. Much more often, the "diabetic foot" syndrome develops against the background of long-term (more than 15 years) diabetes mellitus and mainly in the elderly. In 60% of patients, there is damage to the tarsal and tarsometatarsal joints, in 30% - the metatarsophalangeal joints and in 10% - the ankle joints. In most cases, the process is unilateral and only in 20% of patients - bilateral. Edema, hyperemia of the area of the corresponding joints, deformation of the foot, ankle joint, trophic ulcers of the sole in the absence of almost pain syndrome appear. The detection of the clinical picture of the disease is often preceded by trauma, tendon strain, callus formation with subsequent ulceration, and in case of damage to the ankle joint - a fracture of the lower third of the leg. Radiologically, massive bone destruction with sequestration and resorption of bone tissue, gross violation of the articular surfaces and periarticular hypertrophic changes in soft tissues, subchondral sclerosis, osteophyte formation, intra-articular fractures are detected. Often, a pronounced radiological destructive process is not accompanied by clinical symptoms. In the pathogenesis of neuroarthropathy in the elderly, in addition to polyneuropathy, the ischemia factor takes part, caused by damage to the microcirculation and main vessels. The addition of infection may be accompanied by phlegmon and osteomyelitis.

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Clinical manifestations of neuro-arthropathic and ischemic foot

Neuro-arthropathic	Ischemic foot
Good vascular pulsation Normal tissues of the foot Calluses in places of pressure Decreased or absent Achilles reflex Tendency to Hammer Toe "Falling foot" (steppage) Charcot's deformity Painless ulcers Cheiroarthropathy (Greek cheir - hand)	No pulsation Soft tissue atrophy Thin dry skin Normal Achilles reflex Redness of the feet Paleness of the feet when raising them while lying down Painful ulcers

Another manifestation of neuroarthropathy is diabetic cheiropathy (neuroarthropathy), the prevalence of which is 15-20% in patients with type 1 diabetes mellitus for 10-20 years. The first sign of the syndrome is a change in the skin of the hands. It becomes dry, waxy, compacted and thickened. Then, it becomes difficult and impossible to straighten the little finger, and later other fingers due to joint damage. Neuroarthropathy usually precedes the appearance of chronic complications of diabetes mellitus (retinopathy, nephropathy). The risk of these complications in the presence of neuroarthropathy increases by 4-8 times.

Amyotrophy is a rare form of diabetic neuropathy. The syndrome is characterized by weakness and atrophy of the pelvic girdle muscles, muscle pain, decreased and lost knee reflexes, impaired sensitivity in the femoral nerve area, and isolated fasciculations. The process begins asymmetrically, then becomes bilateral and occurs more often in elderly men with mild diabetes. Electromyography reveals primary muscle pathology and nerve damage. Muscle biopsy reveals atrophy of individual muscle fibers, preservation of transverse striation, absence of inflammatory and necrotic changes, and accumulation of nuclei under the sarcolemma. A similar picture of muscle biopsy is observed in alcoholic myopathy. Diabetic amyotrophy should be differentiated from polymyositis, amyotrophic lateral sclerosis, thyrotoxic myopathy, and other myopathies. The prognosis for diabetic amyotrophy is favorable: recovery usually occurs within 1-2 years or earlier.

The autonomic nervous system regulates the activity of smooth muscles, endocrine glands, heart and blood vessels. Disruption of parasympathetic and sympathetic innervation underlies changes in the function of internal organs and the cardiovascular system. Clinical manifestations of autonomic neuropathy are observed in 30-70% of cases, depending on the examined contingent of patients with diabetes mellitus. Gastrointestinal pathology includes dysfunction of the esophagus, stomach, duodenum and intestines. Dysfunction of the esophagus is expressed in a decrease in its peristalsis, expansion and decrease in the tone of the lower sphincter. Clinically, patients experience dysphagia, heartburn and, occasionally, ulceration of the esophagus. Diabetic gastropathy is observed in patients with a long duration of the disease and is manifested by vomiting food eaten the day before. Radiologically, decreased and paresis of peristalsis, gastric dilation, and slow emptying are detected. In 25% of patients, dilation and decreased tone of the duodenum and its bulb are detected. Secretion and acidity of gastric juice are decreased. In gastric biopsies, signs of diabetic microangiopathy are found, which are combined with the presence of diabetic retinopathy and neuropathy. Diabetic enteropathy is manifested by increased peristalsis of the small intestine and periodic diarrhea, more often at night (the frequency of bowel movements reaches 20-30 times a day). Diabetic diarrhea is usually not accompanied by weight loss. There is no correlation with the type of diabetes and its severity. Inflammatory and other changes were not detected in biopsies of the small intestinal mucosa. The diagnosis is difficult due to the need to differentiate from enteritis of various etiologies, malabsorption syndromes, etc.

Neuropathy (atony) of the urinary bladder is characterized by a decrease in its contractile ability in the form of slow urination, its reduction to 1-2 times a day, the presence of residual urine in the urinary bladder, which contributes to its infection. Differential diagnosis includes hypertrophy of the prostate gland, the presence of tumors in the abdominal cavity, ascites, multiple sclerosis.

Impotence is a common symptom of autonomic neuropathy and may be its only manifestation, observed in 40-50% of patients with diabetes. It may be temporary, for example, during decompensation of diabetes, but later it becomes permanent. There is a decrease in libido, inadequate response, weakening of orgasm. Infertility in men with diabetes may be associated with retrograde ejaculation, when weakness of the sphincters of the bladder leads to the release of sperm into it. In patients with diabetes, impotence is not associated with disorders of the gonadotropic function of the pituitary gland, the testosterone content in the plasma is normal.

Pathology of sweating in the initial stages of diabetes mellitus is expressed in its increase. With increasing duration of the disease, its decrease is observed, up to anhidrosis of the lower extremities. At the same time, in many people, sweating increases in the upper parts of the body (head, neck, chest), especially at night, which simulates hypoglycemia. When studying skin temperature, a violation of the oral-caudal and proximal-distal pattern and reaction to heat and cold is revealed. A peculiar type of autonomic neuropathy is gustatory sweating, which is characterized by profuse sweating in the face, neck, upper chest a few seconds after eating certain foods (cheese, marinade, vinegar, alcohol). It is rare. Localized increased sweating is due to dysfunction of the superior cervical sympathetic ganglion.

Diabetic autonomic cardiac neuropathy (DACN) is characterized by orthostatic hypotension, persistent tachycardia, weak therapeutic effect on it, fixed heart rhythm, hypersensitivity to catecholamines, painless myocardial infarction and sometimes sudden death of the patient. Postural (orthostatic) hypotension is the most obvious sign of autonomic neuropathy. It is expressed in the appearance of dizziness, general weakness, darkening of the eyes or deterioration of vision in patients in a standing position. This symptom complex is often regarded as a hypoglycemic condition, but in combination with a postural drop in blood pressure, its origin is beyond doubt. In 1945, A. Rundles first linked postural hypotension with neuropathy in diabetes. Postural hypotension may be exacerbated by antihypertensives, diuretics, tricyclic antidepressants, phenothiazines, vasodilators, and nitroglycerin. Insulin administration may also worsen postural hypotension by reducing venous return or damaging capillary endothelial permeability with a decrease in plasma volume, while the development of heart failure or nephrotic syndrome reduces hypotension. It is believed that its occurrence is explained by a blunted plasma renin response to standing due to deterioration of the sympathetic innervation of the juxtaglomerular apparatus, as well as a decrease in basal and stimulated (in the standing position) plasma norepinephrine levels, or a baroreceptor defect.

In patients with diabetes mellitus complicated by DVT, at rest, an increase in heart rate to 90-100, and sometimes up to 130 beats/min is observed. Persistent tachycardia, which is not amenable to therapeutic effects in patients with diabetes mellitus, is caused by parasympathetic insufficiency and can serve as a manifestation of the early stage of autonomic cardiac disorders. Vagal innervation of the heart is the cause of the loss of the ability to normally vary the heart rate in diabetic cardiopathy and, as a rule, precedes sympathetic denervation. A decrease in the variation of cardiac intervals at rest can serve as an indicator of the degree of functional disorders of the autonomic nervous system.

Total denervation of the heart is rare and is characterized by a fixed rapid heart rhythm. Typical pains during the development of myocardial infarction are not typical for patients suffering from DIC. In most cases, during it, patients do not feel pain or they feel atypical. It is assumed that the cause of painless infarctions in these patients is damage to the visceral nerves that determine the pain sensitivity of the myocardium.

M. McPage and P. J. Watkins reported 12 cases of sudden "cardiopulmonary arrest" in 8 young individuals with diabetes mellitus and severe autonomic neuropathy. There was no clinical and anatomical evidence of myocardial infarction, cardiac arrhythmia, or hypoglycemic state. In most cases, the cause of the attack was inhalation of a narcotic drug during general anesthesia, the use of other drugs, or bronchopneumonia (5 attacks occurred immediately after administration of anesthesia). Thus, cardiorespiratory arrest is a specific sign of autonomic neuropathy and can be fatal.

Diabetic encephalopathy. Persistent changes in the central nervous system in young people are usually associated with acute metabolic disorders, and in old age are also determined by the severity of the atherosclerotic process in the vessels of the brain. The main clinical manifestations of diabetic encephalopathy are mental disorders and organic cerebral symptoms. Memory is most often impaired in patients with diabetes. Hypoglycemic conditions have a particularly pronounced effect on the development of mnestic disorders. Mental disorders can also manifest themselves as increased fatigue, irritability, apathy, tearfulness, and sleep disorders. Severe mental disorders in diabetes are rare. Organic neurological symptoms can manifest themselves as scattered microsymptoms, indicating diffuse damage to the brain, or as gross organic symptoms indicating the presence of a lesion in the brain. The development of diabetic encephalopathy is determined by the development of degenerative changes in neurons of the brain, especially during hypoglycemic conditions, and ischemic foci in it, associated with the presence of microangiopathy and atherosclerosis.

Skin pathology. Diabetic dermopathy, lipoid necrobiosis and diabetic xanthoma are more typical for patients with diabetes, but none of them are absolutely specific for diabetes.

Dermopathy ("atrophic spots") is expressed in the appearance on the anterior surface of the shins of symmetrical reddish-brown papules with a diameter of 5-12 mm, which then turn into pigmented atrophic spots of the skin. Dermopathy is more often detected in men with a long duration of diabetes mellitus. The pathogenesis of dermopathy is associated with diabetic microangiopathy.

Lipoid necrobiosis is much more common in women and in 90% of cases is localized on one or both shins. In other cases, the affected area is the trunk, arms, face, and head. The incidence of lipoid necrobiosis is 0.1-0.3% of all patients with diabetes. The disease is characterized by the appearance of red-brown or yellow skin areas ranging in size from 0.5 to 25 cm, often oval in shape. The affected areas are surrounded by an erythematous border of dilated vessels. The deposition of lipids and carotene causes the yellow color of the affected areas of the skin. Clinical signs of lipoid necrobiosis may precede the development of type I diabetes mellitus by several years or be detected against its background. As a result of examination of 171 patients with lipoid necrobiosis, a connection of this disease with diabetes mellitus was revealed in 90% of them: in some patients, necrobiosis developed before diabetes mellitus or against its background, while other patients had a hereditary predisposition to it. Histologically, signs of obliterating endarteritis, diabetic microangiopathy and secondary necrobiotic changes are found in the skin. Electron microscopy revealed destruction of elastic fibers, elements of inflammatory reaction in necrotic areas and the appearance of giant cells. One of the causes of lipoid necrobiosis is considered to be increased platelet aggregation under the influence of various stimuli, which, along with endothelial proliferation, causes thrombosis of small vessels.

Diabetic xanthoma develops as a result of hyperlipidemia, with the main role played by the increased content of chylomicrons and triglycerides in the blood. Yellowish plaques are localized mainly on the flexor surfaces of the extremities, chest, neck and face and consist of accumulations of histiocytes and triglycerides. Unlike xanthomas observed in familial hypercholesterolemia, they are usually surrounded by an erythematous border. Elimination of hyperlipidemia leads to the disappearance of diabetic xanthoma.

Diabetic blister is a rare skin lesion in diabetes mellitus. This pathology was first described in 1963 by R. P. Rocca and E. Peregura. Blisters appear suddenly, without redness, on the fingers, toes, and feet. Their sizes vary from a few millimeters to several centimeters. The blister can increase in size over several days. The blister fluid is transparent, sometimes hemorrhagic, and always sterile. Diabetic blister disappears on its own (without opening) within 4-6 weeks. Diabetic blister occurs more frequently in patients with signs of diabetic neuropathy and long duration of diabetes, as well as against the background of diabetic ketoacidosis. Histological examination revealed intradermal, subepidermal, and subcorneal localization of the blister. The pathogenesis of diabetic blister is unknown. It must be differentiated from pemphigus and porphyrin metabolism disorders.

Annular Darier's granuloma may occur in patients with diabetes mellitus ^: elderly, more often in men. On the trunk and limbs, rashes appear in the form of coin-shaped edematous spots of pink or reddish-yellowish color, prone to rapid peripheral growth, fusion and formation of rings and bizarre polycyclic figures, bordered by a dense and raised edge. The color of the central, slightly sunken zone is unchanged. Patients complain of slight itching or burning. The course of the disease is long, recurrent. Usually, the rash disappears after 2-3 weeks, and new ones appear in their place. Histologically, edema, vasodilation, perivascular infiltrates of neutrophils, histiocytes, lymphocytes are detected. The pathogenesis of the disease has not been established. Allergic reactions to sulfanilamide and other drugs can serve as provoking factors.

Vitiligo (depigmented symmetrical areas of skin) is detected in patients with diabetes in 4.8% of cases compared to 0.7% in the general population, and in women 2 times more often. Vitiligo is usually combined with diabetes mellitus type I, which confirms the autoimmune genesis of both diseases.

Much more often than with other diseases, diabetes mellitus is accompanied by furuncles and carbuncles, which usually occur against the background of decompensation of the disease, but can also be a manifestation of latent diabetes or precede impaired glucose tolerance. A greater tendency of diabetics to fungal diseases is expressed in the manifestations of epidermophytosis, found mainly in the interdigital spaces of the feet. More often than in people with intact glucose tolerance, itchy dermatoses, eczema, and itching in the genital area are detected. The pathogenesis of this skin pathology is associated with a violation of intracellular glucose metabolism and a decrease in resistance to infection.

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Pathology of the organ of vision in diabetes mellitus

Various disorders of the visual organ function, including blindness, are found in patients with diabetes mellitus 25 times more often than in the general population. Among patients suffering from blindness, 7% are patients with diabetes mellitus. Disorders of the visual organ function can be caused by damage to the retina, iris, cornea: lens, optic nerve, extraocular muscles, orbital tissue, etc.

Diabetic retinopathy is one of the main causes of visual impairment and blindness in patients. Various manifestations (against the background of 20-year duration of diabetes mellitus) are detected in 60-80% of patients. Among patients with type I diabetes with a disease duration of more than 15 years, this complication is observed in 63-65%, of which proliferating retinopathy - in 18-20% and complete blindness - in 2%. In patients with type II diabetes, its signs develop with a shorter duration of diabetes. Significant visual impairment affects 7.5% of patients, and complete blindness occurs in half of them. A risk factor for the development and progression of diabetic retinopathy is the duration of diabetes mellitus, since there is a direct correlation between the frequency of this syndrome and the duration of type I diabetes. According to V. Klein et al., when examining 995 patients, it was found that the frequency of visual impairment increases from 17% in patients with a diabetes duration of no more than 5 years, to 97.5% with a duration of up to 10-15 years. According to other authors, cases of retinopathy fluctuate up to 5% during the first 5 years of the disease, up to 80% - with a diabetes duration of more than 25 years.

In children, regardless of the duration of the disease and the degree of its compensation, retinopathy is detected much less frequently and only in the postpubertal period. This fact allows us to assume a protective role of hormonal factors (STH, somatomedin "C"). The probability of optic disc edema also increases with the duration of diabetes: up to 5 years - its absence and after 20 years - 21% of cases; on average, it is 9.5%. Diabetic retinopathy is characterized by dilation of venules, the appearance of microaneurysms, exudates, hemorrhages and proliferating retinitis. Microaneurysms of capillaries and, especially, venules are specific changes in the retina in diabetes mellitus. The mechanism of their formation is associated with tissue hypoxia caused by metabolic disorders. A characteristic tendency is the increase in the number of microaneurysms in the premacular region. Long-existing microaneurysms may disappear, which is caused by their rupture (hemorrhage) or thrombosis and organization due to the deposition of proteins of hyaline-like material and lipids in them. Exudates in the form of white-yellow, waxy foci of opacification are usually localized in the area of hemorrhages in various parts of the retina. Approximately 25% of patients with diabetic retinopathy have changes in the form of proliferating retinitis. Usually, against the background of microaneurysms, hemorrhages in the retina and exudates, they develop hemorrhages in the vitreous body, which is accompanied by the formation of connective tissue-vascular proliferative strands penetrating from the retina into the vitreous body. Subsequent wrinkling of the connective tissue causes retinal detachment and blindness. The process of formation of new vessels also occurs in the retina, with a tendency to damage the optic disc, which causes a decrease or complete loss of vision. Proliferating retinitis has a direct correlation with the duration of diabetes mellitus. Its signs are usually detected 15 years after the detection of diabetes mellitus in young patients and 6-10 years after in adults. A significant frequency of this complication is observed with a long duration of the disease in patients who fell ill at a young age. In many patients, proliferating retinitis is combined with clinical manifestations of diabetic nephropathy.

According to the modern classification (by E. Kohner and M. Porta), there are three stages of diabetic retinopathy. Stage I is non-proliferative retinopathy. It is characterized by the presence of microaneurysms, hemorrhages, retinal edema, and exudative foci in the retina. Stage II is preproliferative retinopathy. It is characterized by the presence of venous anomalies (beading, tortuosity, doubling, and/or pronounced fluctuations in the caliber of vessels), a large number of hard and "cotton wool" exudates, intraretinal microvascular anomalies, and multiple large retinal hemorrhages. Stage III is proliferative retinopathy.

Characterized by neovascularization of the optic nerve head and/or other parts of the retina, vitreous hemorrhages with the formation of fibrous tissue in the area of preretinal hemorrhages. The cause of blindness in patients with diabetes mellitus is vitreous hemorrhage, maculopathy, retinal detachment, glaucoma and cataracts.

Diabetic retinopathy (including proliferative retinopathy) is characterized by a wave-like course with a tendency to spontaneous remissions and periodic exacerbation of the process. The progression of retinopathy is facilitated by decompensation of diabetes mellitus, arterial hypertension, renal failure and, to a significant extent, pregnancy, as well as hypoglycemia. Diseases of the eyelids (blepharitis, cholazion, styes) are not specific to diabetes mellitus, but are often combined with it and are characterized by a persistent relapsing course caused by a violation of tissue glucose metabolism and a decrease in the immunobiological properties of the body.

Changes in the conjunctival vessels in patients with diabetes are expressed in the presence of phlebopathy (lengthening and expansion of the venular ends of capillaries, microaneurysms) and sometimes exudates.

Corneal changes are expressed in epithelial punctate keratodystrophy, fibrous and uveal keratitis, recurrent corneal ulcers, which usually do not cause a significant decrease in vision. With insufficient compensation of diabetes mellitus, deposition of glycogen-like material in the pigment epithelium of the posterior surface of the iris is sometimes observed, which causes degenerative changes and depigmentation of the corresponding areas. Against the background of proliferative retinopathy, 4-6% of patients have rubeosis of the iris, expressed in the proliferation of newly formed vessels on its anterior surface and the anterior chamber of the eye, which can be the cause of hemorrhagic glaucoma.

Cataracts are divided into metabolic (diabetic) and senile varieties. The first develops in poorly compensated insulin-dependent patients and is localized in the subcapsular layers of the lens. The second - in elderly people, both diabetics and healthy people, but matures much faster in the former, which explains the need for more frequent surgical interventions. The pathogenesis of diabetic cataracts is associated with increased conversion of glucose to sorbitol in the lens tissues against the background of hyperglycemia. Their excess accumulation causes cellular edema, which directly or indirectly changes the metabolism of myonosite, which leads to the development of cataracts.

Glaucoma occurs in 5% of patients with diabetes mellitus compared to 2% of healthy people. An increase in intraocular pressure by more than 20 mm Hg can damage the function of the optic nerve and cause visual impairment. Diabetes mellitus is often combined with various types of glaucoma (open-angle, narrow-angle, and due to proliferative retinopathy). The open-angle form is typical for patients, characterized by difficult outflow of chamber moisture due to obliteration of the drainage apparatus of the eye. Changes in it (Schlemm's canal) are similar to manifestations of diabetic microangiopathy.

Impaired function of the oculomotor muscles (ophthalmoplegia) is caused by damage to the III, IV and VI pairs of cranial oculomotor nerves. The most characteristic signs are diplopia and ptosis, which are more common in patients with type I diabetes. In some cases, ptosis and diplopia may be the first manifestations of clinical diabetes. The cause of ophthalmoplegia is diabetic mononeuropathy.

Transient visual acuity impairment is observed in patients with diabetes mellitus during initial insulin treatment due to significant fluctuations in glycemia, and also as one of the signs preceding the development of cataracts. Uncompensated diabetes with significantly pronounced hyperglycemia is accompanied by increased refraction due to an increase in the refractive power of the lens. As a rule, myopia develops before the development of cataracts. The above changes in visual acuity can be largely due to the accumulation of sorbitol and fluid in the lens. It is known that hyperglycemia increases the conversion of glucose into sorbitol in the lens, which has a pronounced osmolarity that promotes fluid retention. This in turn can cause changes in the shape of the lens and its refractive properties. A decrease in glycemia, especially during insulin treatment, often contributes to a weakening of refraction. In the pathogenesis of the indicated disorders, a decrease in the secretion of fluid in the anterior chamber is also possible, which contributes to a change in the position of the lens.

Orbital tissue lesions are rare and are caused by bacterial or fungal infections. Both orbital and periorbital tissues are involved in the process. Patients experience proptosis of the eyeball, ophthalmoplegia (up to central fixation of the gaze), deterioration of vision, and pain syndrome. Involvement of the cavernous sinus in the process poses a great danger to life. Treatment is conservative - with antibacterial and antifungal drugs.

Optic nerve atrophy is not a direct consequence of diabetes, but is observed in patients with a long duration of the disease in the presence of diabetic proliferative retinopathy and glaucoma.

To diagnose the pathology of the visual organ, it is necessary to determine its acuity and fields, using biomicroscopy of the anterior part of the eye to identify vascular changes in the conjunctiva, limbus, iris and the degree of opacity of the lens. Direct ophthalmoscopy, fluorescent angiography allow to assess the condition of the retinal vessels. Patients with diabetes mellitus need repeated examinations by an ophthalmologist 1-2 times a year.

Heart damage in diabetes mellitus

Cardiovascular pathology is the main factor causing high mortality in patients with diabetes mellitus. Heart damage in the disease can be caused by diabetic microangiopathy, myocardial dystrophy, autonomic diabetic cardiac neuropathy, and coronary atherosclerosis. In addition, patients with diabetes mellitus are much more likely than patients without diabetes to develop bacterial endocarditis, myocardial abscesses against the background of sepsis, pericarditis in chronic renal failure, and hypokalemic myocarditis in ketoacidosis.

Specific for diabetes mellitus lesion of microcirculatory bed vessels - diabetic microangiopathy - is also found in the heart muscle. This process is histologically characterized by thickening of the basement membrane of capillaries, venules and arterioles, proliferation of endothelium, appearance of aneurysms. Excessive deposition of PAS-positive substances, premature aging of pericytes, accumulation of collagen participate in the pathogenesis of thickening of the basement membrane. Diabetic microangiopathy found in the myocardium contributes to the disruption of its functional activity.

Among patients with idiopathic microcardiopathy, the relative frequency of patients with diabetes mellitus is significantly increased. In this case, damage to small vessels is detected (with unchanged large coronary arteries), extravascular accumulation of collagen, triglycerides and cholesterol between myofibrils, which is not accompanied by hyperlipidemia. Clinically, myocardiopathy is characterized by shortening of the left ventricular ejection period, prolongation of the strain period, and an increase in diastolic volume. Changes characteristic of myocardiopathy can contribute to the frequent occurrence of heart failure during the acute period of myocardial infarction and high mortality. The pathogenesis of diabetic myocardial dystrophy is due to metabolic disorders that are absent in healthy individuals and well-compensated patients with diabetes mellitus. Absolute or relative insulin deficiency disrupts glucose transport across the cell membrane, so most of the myocardial energy expenditure is replenished by increased utilization of free fatty acids, which are formed during increased lipolysis (under conditions of insulin deficiency). Insufficient oxidation of free fatty acids is accompanied by increased accumulation of triglycerides. An increase in the tissue level of glucose-6-phosphate and fructose-6-phosphate causes accumulation of glycogen and polysaccharides in the cardiac muscle. Compensation for diabetes helps to normalize metabolic processes in the myocardium and improve its functional indices.

Diabetic autonomic cardiac neuropathy is one of the clinical manifestations of diabetic vegetative neuropathy, which also includes gastropathy syndrome, enteropathy, bladder atony, impotence and sweating disorder. DVCN is characterized by a number of specific signs, including constant tachycardia, fixed heart rhythm, orthostatic hypotension, hypersensitivity to catecholamines, painless myocardial infarction and "cardiopulmonary arrest" syndrome. It is caused by damage to the parasympathetic and sympathetic divisions of the central nervous system. Initially, parasympathetic innervation of the heart is impaired, which is manifested in the previously mentioned tachycardia up to 90-100 beats/min, and in some cases up to 130 beats/min, which is poorly amenable to therapeutic effects. Weakening of the vagus function is also the cause of disturbance of the heart rhythm regulation, manifested in the absence of respiratory variation of cardiac intervals. The damage to the sensory nerve fibers also explains the relatively frequent myocardial infarctions in these patients with atypical clinical symptoms characterized by the absence or weak expression of pain syndrome. With an increase in the duration of diabetes mellitus, changes in the sympathetic innervation of the smooth muscle fibers of the peripheral vessels join parasympathetic disorders, which is expressed in the appearance of orthostatic hypotension in patients. In this case, patients feel dizziness, darkening in the eyes and flickering "flies". This condition passes on its own, or the patient is forced to take the initial position. According to A. R. Olshan et al., orthostatic hypotension in patients occurs due to a decrease in the sensitivity of baroreceptors. N. Oikawa et al. believe that in response to standing up, there is a decrease in the level of plasma adrenaline.

Another rather rare manifestation of parasympathetic insufficiency is cardiopulmonary insufficiency described by M. McPage and P.J. Watkins in patients suffering from diabetes mellitus type I, and characterized by sudden cessation of cardiac activity and respiration. Of the 8 patients described, 3 died during this condition. In most cases, the cause of death is the inhalation of a narcotic analgesic during pain relief for surgery. At autopsy, its cause was not established in the deceased. Cardiopulmonary arrest, according to the authors, has a primary pulmonary origin due to a decrease in the sensitivity of the respiratory center and hypoxia in patients with autonomic neuropathy, since the carotid bodies and chemoreceptors are innervated by the glossopharyngeal and vagus nerves. As a result of hypoxia, hypotension occurs, cerebral blood flow decreases, and respiratory arrest of central genesis occurs, which is confirmed by the rapid response of patients to respiratory stimulants. Tests that reveal parasympathetic system disorders are based on decreasing the variation of cardiac intervals (decreasing respiratory arrhythmia) caused by the previously described changes in the nervous tissue. The most frequently used tests for this purpose are those that record changes in the heart rhythm during normal and deep breathing, a modified Valsalva test, the Ewing test, and some others. Disorders of the sympathetic innervation of the heart are revealed using an orthostatic test and other tests. All of the listed diagnostic methods are relatively easy to perform, noninvasive, and fairly informative. They can be recommended for use both in hospitals and outpatient settings.

Coronary artery atherosclerosis. The localization of coronary atherosclerosis in patients with diabetes mellitus is the same as in patients without diabetes, and is manifested by the predominant involvement of the proximal coronary arteries. The only difference is the occurrence of coronary atherosclerosis in patients with diabetes mellitus at a young age with a more severe manifestation. Apparently, in diabetes there are significantly fewer collaterals, since the angiography data of the main coronary arteries in patients with coronary sclerosis in the presence and absence of diabetes are the same. According to experimental studies, it is believed that the leading role in the rapid progression of atherosclerosis in patients with diabetes is played by endogenous or exogenous hyperinsulinemia: insulin, suppressing lipolysis, increases the synthesis of cholesterol, phospholipids and triglycerides in the walls of blood vessels. The permeability of insulin-resistant endothelial cells changes under the influence of catecholamines (against the background of glycemic fluctuations), which promotes contact of insulin with smooth muscle cells of the arterial walls, which stimulates the proliferation of these cells and the synthesis of connective tissue in the vascular wall. Lipoproteins are captured by smooth muscle cells and penetrate into the extracellular space, where they form atherosclerotic plaques. This hypothesis explains the threshold relationship between blood glucose levels and atherosclerosis, as well as the fact that risk factors equally affect the development of atherosclerosis in patients with diabetes and in healthy people. It is known that type II of the disease is characterized by an increase in the basal level of insulin and an increase in the incidence of atherosclerosis and coronary heart disease (CHD). When comparing patients with diabetes mellitus and ischemic heart disease with patients with diabetes mellitus without it, an increase in the insulin response to oral glucose administration and a more pronounced increase in insulin secretion after an oral test with tolbutamide were found. In type II diabetes combined with atherosclerosis, the insulin/glucose ratio is increased. As a result of studying patients with atherosclerosis of the coronary, cerebral and peripheral arteries without diabetes, an increase in the insulin response to an oral glucose load was also found. Obesity is accompanied by hyperinsulinemia both in the absence and in the presence of diabetes mellitus. The risk of ischemic heart disease is significantly higher in the presence of android obesity.

Myocardial infarction. Compared with its prevalence in the population, it occurs in patients with diabetes of the same age twice as often. Coronary artery disease is the main cause of death in patients with type II diabetes. Mortality due to myocardial infarction in such patients is extremely high and reaches 38% in the first days after its occurrence, and 75% over the next 5 years. The clinical course of infarction in patients with diabetes has the following features: occurrence of extensive infarctions, frequently observed thromboembolic complications of heart failure, prevalence of repeated infarctions and increased mortality rate in the acute period and often atypical clinical picture of infarction with mild and absent pain syndrome. The frequency of this complication directly correlates with the duration of diabetes (especially in patients with type I), the age of the patients, the presence of obesity, hypertension, hyperlipidemia and, to a lesser extent, with the severity of diabetes and the nature of its treatment. In many cases, type II diabetes debuts with myocardial infarction.

The greatest difficulties in its diagnosis are atypical manifestations. About 42% of patients during myocardial infarction do not feel pain syndrome (compared to 6% of patients without diabetes) or it is atypical and weakly expressed. Signs of infarction in patients with diabetes may be sudden onset of general failure, pulmonary edema, unmotivated nausea and vomiting, decompensation of diabetes mellitus with increased glycemia and ketoacidosis of unknown genesis, cardiac arrhythmia. Studies of patients with diabetes who died from myocardial infarction showed that 30% of them had previously suffered an undiagnosed infarction, and 6.5% had changes indicating 2 or more previously suffered painless infarctions. The Framingham study data indicate that infarction detected by incidental ECG examination was observed in 39% of patients with diabetes and 22% of patients without it. The occurrence of painless myocardial infarctions in diabetes mellitus is currently often associated with autonomic cardiac neuropathy and damage to the sensory fibers of the afferent nerves. This hypothesis was confirmed by studying the nerve fibers of patients who died during a painless infarction. In the control group of deceased (patients with and without painful infarction, with or without diabetes), similar changes were not found at autopsy.

In the acute period of myocardial infarction, 65-100% of patients have basal hyperglycemia, which may be the result of the release of catecholamines and glucocorticoids in response to a stressful situation. The significant increase in endogenous insulin secretion observed in this case does not eliminate hyperglycemia, since this increases the content of free fatty acids in the blood, suppressing the biological effect of insulin. Impaired carbohydrate tolerance in the acute period of myocardial infarction is often transient, but almost always indicates the risk of developing diabetes mellitus. Subsequent examination (after 1-5 years) of patients with transient hyperglycemia in the acute period of infarction indicates that 32-80% of them were subsequently diagnosed with NTG or clinical diabetes.

Kidney damage in diabetes

Diabetic nephropathy (Kimmelstiel-Wilson syndrome, intercapillary glomerulosclerosis) is a manifestation of late diabetic syndrome. It is based on various processes, including nodular and diffuse glomerulosclerosis, thickening of the basal membrane of the glomerular capillaries, arterio- and arteriolosclerosis, and tubular-interstitial fibrosis.

This complication is one of the main causes of mortality among patients with diabetes mellitus, increasing it by 17 times compared to the general population. In about half of all cases, diabetic nephropathy develops in patients who developed diabetes mellitus before the age of 20. Its clinical manifestations are detected after 12-20 years of the disease. However, some changes in kidney function and anatomical disorders develop much earlier. Thus, already with the onset of diabetes mellitus, an increase in the size of the kidneys, the lumen of the tubules and the rate of glomerular filtration is observed. After compensation for diabetes, the size of the kidneys normalizes, but the rate of glomerular filtration remains elevated even after 2-5 years, when a puncture biopsy reveals thickening of the basal membrane of the glomerular capillaries, which indicates the initial (histological) stage of diabetic nephropathy. Clinically, no other changes are observed in patients during a 12-18-year period, despite the progression of anatomical disorders.

The first symptom of diabetic nephropathy is transient proteinuria, which usually occurs during physical exertion or orthostasis. Then it becomes constant with normal or slightly reduced glomerular filtration rate. A significant increase in proteinuria, exceeding 3 g/day and sometimes reaching 3 g/l, is accompanied by dysproteinemia, characterized by hypoalbuminemia, decreased IgG, hypergammaglobulinemia and increased alpha2-macroglobulins. At the same time, 40-50% of Volnykh develop nephrotic syndrome, hyperlipidemia appears according to type IV according to Friedrichsen. After 2-3 years of constant proteinuria, azotemia appears, the content of urea and creatinine in the blood increases, and glomerular filtration decreases.

Further progression of the disease leads after another 2-3 years to the development of clinical syndrome of renal failure in half of the patients, especially rapid increase in the number is observed in patients with pronounced proteinuria in combination with nephrotic syndrome. With the development of renal failure, the rate of glomerular filtration decreases sharply, the levels of residual nitrogen (more than 100 mg%) and creatinine (more than 10 mg%) increase, hypo- or normochromic anemia is detected. In 80-90% of patients at this stage of the disease, arterial pressure increases significantly. The genesis of arterial hypertension is caused mainly by sodium retention and hypervolemia. Severe arterial hypertension can be combined with heart failure of the right ventricular type or complicated by pulmonary edema.

Renal failure is usually accompanied by hyperkalemia, which can reach 6 mmol/l or more, which is manifested by characteristic ECG changes. Its pathogenesis can be caused by extrarenal and renal mechanisms. The former include a decrease in the content of insulin, aldosterone, norepinephrine and hyperosmolarity, metabolic acidosis, beta-blockers. The latter include a decrease in glomerular filtration, interstitial nephritis, hyporeninemic hypoaldosteronism, prostaglandin inhibitors (indomethacin) and aldactone.

The clinical course of diabetic nephropathy is complicated by urinary tract infection, chronic pyelonephritis, which contributes to the development of interstitial nephritis. Chronic pyelonephritis is often asymptomatic and manifests itself as a deterioration in the clinical course of diabetic nephropathy or decompensation of diabetes mellitus. The latter (according to autopsy data - 110%) is combined with necrotic papillitis, which can manifest itself in a severe form (1%) with an increase in body temperature, macrohematuria, renal colic, as well as in a latent form, often undiagnosed, since its only manifestation is microhematuria. In some patients with renal failure, the course of diabetes mellitus changes, which is expressed in a decrease in the daily requirement for insulin, due to a decrease in the appetite of patients due to nausea and vomiting, as well as in connection with a decrease in insulin degradation in the kidneys and an increase in its half-life.

The clinical course and manifestation of diabetic nephropathy in patients with type I and type II diabetes have significant differences. In type II diabetes, nephropathy progresses much more slowly and is not the main cause of death.

The peculiarities of the clinical manifestation of diabetic nephropathy in different types of diabetes are apparently due to the varying degree of participation in its pathogenesis of reversible or irreversible changes in renal tissue.

Pathogenesis of diabetic nephropathy according to D'Elia.

Reversible changes

1. Increased glomerular filtration without an increase in renal plasma flow.
2. Proteinuria with hyperglycemia, insulin deficiency, increasing with physical exertion and orthostasis.
3. Accumulation of immunoglobulins, protein breakdown products, and mesangial hyperplasia in the mesangium.
4. Decreased ability of the distal tubules to secrete hydrogen ions.

Irreversible changes

1. Increased collagen synthesis in the basement membrane.
2. Hyaline sclerosis of arterioles with damage to the juxtaglomerular apparatus.
3. Atherosclerosis of the arteries with kidney damage.
4. Papillary necrosis.

According to the nature of the clinical course, diabetic nephropathy is divided into latent, clinically manifested, and terminal forms. The latter is characterized by uremia. When dividing nephropathy into stages, the Mogensen classification (1983) is used, which is based on laboratory and clinical data.

1. The hyperfunction stage occurs at the onset of diabetes mellitus and is characterized by hyperfiltration, hyperperfusion, renal hypertrophy and normoalbuminuria (<30 mg/day).
2. Stage of initial kidney changes. Characterized by thickening of the glomerular basement membrane, mesangium expansion, hyperfiltration and normoalbuminuria (<30 mg/day). These changes occur when diabetes mellitus lasts for more than 5 years.
3. The stage of incipient DN develops after 5 years or more. It is characterized by the appearance of microalbuminuria (from 30 to 300 mg/day), normal or increased SCF.
4. The stage of pronounced DN occurs after 10-15 years of diabetes. Characteristic are proteinuria (more than 0.5 g of protein per day), arterial hypertension, and decreased SCF. These signs are due to sclerosis of 50-70% of the glomeruli.
5. Stage of chronic renal failure (uremia). In this case, the SCF decreases (<10 ml/min). Changes in the kidneys correspond to total glomerulosclerosis, which develops with a duration of diabetes of 15-20 years.

Stages I-III of diabetic nephropathy represent preclinical forms of the disease.

Stage IV of diabetic nephropathy is characterized by the appearance of proteinuria, decreased renal concentrating ability, hypoisosthenuria, edema, persistent hypoproteinemia, hyperlipidemia, and increased blood pressure. At the same time, the nitrogen-excreting function is reduced.

Stage V of diabetic nephropathy is the nephrosclerotic stage, which is expressed in chronic renal failure of the III degree (edema, hypertension, hypoisosthenuria, cylindruria, erythrocyturia, creatinemia, azotemia, increased blood urea levels, uremia). An "improvement" in the course of diabetes mellitus is characteristic: glucosuria, hyperglycemia, and daily insulin requirements decrease, which is due to a decrease in the activity of the insulinase enzyme in the kidneys, which normally breaks down insulin. Nephropathy (stages IV-V) is usually combined with diabetic retinopathy of stages II and III.