Etiology and pathogenesis of insulin nondependent diabetes mellitus 


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Etiology and pathogenesis of insulin nondependent diabetes mellitus



A genetic factor has a large value in development of INDDM. Inherited predisposition is more important of this type of diabetes than in IDDM with concordance for NIDDM approaching 100%. Risk of development of disease increased from twofold to sixfold at presence of NIDDM at parents or close relatives. However the certain genetic defect is still unknown.

NIDDM is commonly associated with several other disorders such as obesity, hypertension and hyperlipidemia, so-called metabolic syndrome. The patients arc often obese or have been obese in the past and have typically been physically inactive. The risk of development of INDDM at obesity 1 degree is increased in 2 times, at II degree - in 5 times, and at III degree - more than in 10 times. Obesity especially abdominal type, acts as a diabetogenic factors through increasing resistance to the action of insulin. Epidemiologic studies of NIDDM provide evidence that food of these patients arc diabetigenic features and content the high caloric easy absorbed carbohydrates, sweets, alcohol and deficit of vegetable cellulose. Such lifestyle factor, as over-eating, especially when combined with obesity and under activity lead lo development of NIDDM.

Ageing is an important risk factor for NIDDM because the disease mainly develops after middle age, in contrast to IDDM, which commonly affects younger people.

Pathogenesis of NIDDM connected with combination decreased insulin secretion and decreased insulin sensitivity. Early stage of NIDDM is characterized by insulin resistance which means the reduced sensitiveness of peripheral tissue commonly skeletal muscle to insulin. There are three levels of insulin resistance: pre-receptor, receptor and post receptor. Pre-receptor insulin resistance is related lo production of inactive insulin molecule or disturbances of proinsulin transformation in insulin with store an excess amount of proinsulin which is biologically inactive. Receptor insulin resistance is due to the synthesis of abnormally inactive receptors to insulin in target organs (liver, fat and muscle) results in appearance of antibodies to the insulin receptors. Post receptor insulin resistance is characterized by reduced metabolic activity of insulin in cells due to decreased tirozin kinase activity. In development of insulin resistance take part circulating in blood antagonists to insulin such as antibodies and contrinsulin hormones - cortisol, thyroid hormone, glucagons, catecholamines, prolactin. Thus insulin resistance may be to one of three general causes: an abnormal insulin molecule, an excessive amount of circulating antagonists and target tissue disturbances.

Clinical features

The symptoms and signs of diabetes may be divided into three group regards to main metabolic consequences of lack of insulin (hyperglycemia); specific long-term complications of diabetes (microangiopathy); including retinopathy with potential blindness, nephropathy with a risk of progression to renal failure, nephropathy with a risk for foot ulcers, amputation, and Charcot joints and autonomic dysfunction such as sexual impairment; acceleration of comorbid pathology due to diabetes (atherosclerosis, infections). Thus DM is associated with development of specific long-term organ damage (diabetes complication).

Symptoms of hyperglycemia. When the concentration of glucose in the plasma exceeds the renal threshold glucosuria occurs. In case of consistent glucosuria (generally >180 mg/dl or 10, 0 mM throughout the day and night) the classical symptoms of diabetes appear: polydipsia, polyuria and polyphagia which is related directly to the degree of glucosuria. Polydipsia is accompanied by thirst and dryness in the mouth. In the period decompensation patient can drink more than 5 liters of water in day, quite often he drink a lot of water at night.

Characteristic of diabetes is increased appetite (polyphagia). Nevertheless inspite the increased of food intake, such patients lose weight because of the loss of glucose in the urine. Weight loss is specific features for patients with IDDM and not expressed or absent at NIDDM which, as a rule, is accompanied by obesity. Polyphagia goes down sharply during severe decompensation, commonly at ketoacidosis. Frequent and abundant urination (polyuria and pollakiuria) both in the day and night time present at diabetic patients. Osmotic diuresis due to lack of insulin may contribute to pathophysiology of polydipsia and polyuria. Increased catabolism lead to augmentation of glycogenolysis, gluconeogenesis, lipolysis result in protein wasting and increased urinary nitrogen loss. These changes in protein and fat metabolism contribute to wasting, loss of weight, growth retardation in children. Protein wasting in patients with uncontrolled diabetes may be responsible for general and muscle weakness, poor wound healing. Sharp changes of glucose concentration and plasma osmolarity may cause visual blurring. Persistent glucosuria is frequently accompanied by skin itching, in women in region of genitals due to vulvovaginitis with odorous vaginal discharge.

The specific symptoms related 10 diabetic macroangiopathy correspond with affection of retina, kidneys, nervous system. The main complaints are partial an temporary impairment of vision and even blindness, appearance of edema due to the nephritic syndrome as evidence of diabetic nephrophaty, change of diuresis at initial stage in a form of polyuria, later oliguria. In stage of renal failure - appear anuria. Involvement of the nervous system in diabetes gives such clinical manifestations: numbness, tingling, parcsthesias, burning and sharp pain in the distal portions of the lower extremities, less frequently of the upper extremities. Abnormalities of the autonomic nervous system occur in patients with long-standing diabetes with involvement cardiovascular, gastrointestinal, urogenital systems. The patients complain on palpitation escape beat, nausea, vomiting, dysphagia, diarrhea, urinary incontinence, failure to empty the urinary bladder fully. Impotence presents in 40 % of diabetic patients.

At early stage of diabetes are there metabolic abnormalities which serve as pathophysiological basis for increased predisposition to atherosclerosis of different vessels: coronary, peripheral. Coronary artery disease occurs more frequently in diabetic patients compared with general population. Clinical manifestation of comorbid pathology is chest pain different duration and intensity, arrhythmia. Atherosclerotic affection of peripheral vessels commonly low extremities is characterized by intermitted claudication and in more severe vessel occlusion, pain at rest.

Objective examination. The patient conditiondepends on stage of disease and evidence of complications. In early stage of disease the patient' condition is satisfactory. As a result of diabetic nephropathy, renal failure, visual impairment, clinical signs of neuropathy, cardiovascular disorders the condition becomes grave and even extremely grave in case of diabetic ketoacidosis, which characterized by passive position and unconsciousness. There are some features of diabetic der-mopathy as a direct result of metabolic abnormalities: dryness of skin, decreased turgor and elasticity, shiny spots, scaly patches, diabetic bullae which located in the pretibial area. In diabetic patients with marked hypertryglyceridemia may observe eruptive xanthomas, which located in the elbow, shin; knees, buttocks and posterior thigh areas. In area of eyelids quite often it is possible to find xantelasm yellow spots with content of lipid. Red-brown papulae are observed on the skin of shins, later transformed in pigmental atrophy spots. In case of dilation of skin capillaries the hyperemia of skin in area of cheek and neck are appeared so called diabetic blush. Infectious complications of skin lead to furuncules which in diabetic patients progress to disseminated process with formation carbuncules. Some factors ischemia, peripheral polyneuropathy and infections cause fool under, cellulitis and gangrene. Neuropathic ulcers may appear in the areas of callus formation. Changes of joints related lo neuropathic arthrophaty occur at the ankle or in the foot at the tarsometatarsal or metatarsophalangeal joints. So called Charcot`s joints are characterized by unilateral painless swelling, erythema in association with joint instability.

Affection of the respiratory system in diabetes may assume progressive and threatening forms due to the infections. Patients with diabetes are predisposed to tuberculosis which progresses very rapidly. Prognosis for diabetic patients is worse than for nondiabetic person in case of tuberculosis. Infections of various types lead to complications such as nasal sinusitis with purulent process and gangrene of the nasal mucous membrane, bronchitis, pneumonia.

Affection of the cardiovascular system may take the form of diabetic cardio-myopathy and coronary heart disease due to the acceleration of atherosclerotic process. Clinically diabetic cardiomyopathy may manifests as chest pain and features of congestive heart failure: dyspnea, cough, and edema. Decreased ventricular ejection fraction is revealed by echocardiography and radionuclide ventriculography.

Arterial hypertension as a rule has secondary origin as a sign of diabetic nephropathy, chronic pyelonephritis, atherosclerosis of kidney arteries, cerebral atherosclerosis. Patients with diabetes are at a particularly high risk for cardiovascular, cerebrovascular and peripheral artery disease relevant to atherosclerosis. The risk of myocardial infarction and sudden death are higher twofold in diabetic patients as compare with nondiabetic population. Myocardial infarction occurs at young age, has severe course and poor outcomes, complicated by cardiogenic shock, thromboembolism of pulmonary artery, aneurism of left ventricle. Period of rehabilitation lasts longer and myocardial remodeling more frequent results in development of heart failure. A greater prevalence of “silent” myocardial infarction among diabetic patients have been revealed. Death rate relevant to myocardial infarction account on the average 38-50 % at patients with diabetes.

The factors responsible for the accelerated atherosclerosis in the diabetic population are hypercholesterolemia, hypertriglyceridemia, increased concentration of low density lipoproteins, reduced concentration of high density lipoproteins, increased adhesiveness and sensitivity to aggregating agents. Cluster of impaired glucose homeostasis, abdominal obesity, hyperlipidemia and hypertension have been described as metabolic syndrome with specific entity "dead quartet". This term considered the meaning of metabolic abnormalities as crucial factors for atherosclerosis and vascular complication more commonly in NIDDM. It seems likely that insulin resistance being the primary defect of metabolic syndrome.

Signs of peripheral atherosclerosis may include diminished or impalpable pulses in the feel, bruits over the carotid or femoral arteries. According to the atherosclerotic occlusion of tibiae and popliteal arteries occurs vascular impairment in the leg and/or foot with development of ulcer and gangrene. Infected necrotic lesions, complicated by cellulites, osteomylitis and generalized septicemia required surgical amputation.

Gastrointestinal disorders at diabetes are explained by decreased motility with distension of stomach and gallbladder which clinically are manifested by poor esophageal contraction, diarrhea, "blind loop" syndrome, malabsorption. Hepatomegaly due to marked fatty infiltration of the liver is observed in patients with decompensated diabetes.

The most dangerous complication of both IDDM and NIDDM is diabetic nephropathy, which responsible for development or renal failure and is a major cause of morbidity and mortality in the diabetic population. The earliest clinical manifestation is microalbuminuria which is defined as an increase in urinary albumin measurable by radioimmune assay. Further progression from early stage to overt diabetic nephropathy is manifested by gross proteinuria in excess of 500 mg/24 h. The proteinuria may reach massive proportions, resulting in the nephritic syndrome with hypoalbuminemia and edema. The course of diabetic nephropathy is complicated by the presence of symptomatic hypertension. The outcomes of nephropathy are renal failure.

Urogenital dysfunction results from incompetence of internal vesicle sphincter, dilation of urine bladder, accompanied by chronic recurrent urinary tract infections: pyelonephritis, cystitis. In women the vulvovaginitis is detected. The women in fertile age are predisposed to reproductive dysfunction and have an increased incidence of stillborn, abnormally large and heavy babies and babies with congenital defects.

Involvement of the nervous system in diabetes has been described as clinical specific syndrome of diabetic neuropathy. Another reason of nervous dysfunction is a consequence of accelerated atherosclerosis leading to infarction of a spinal or cerebral artery. The various forms of diabetic neuropathy may be divided into three major clinical groups: symmetric peripheral polyneuropathy, mononeuropathy and autonomic neuropathy. The main signs of diabetic neuropathy are loss of vibratory sensation dislally in the legs, depression or loss of the tendon reflexes at the ankles. Deep and penetrating neuropathic ulcers at the feet may develop. In case of mononeurupathy muscle atrophy may arise.

One of the serious complications of diabetes is retinopathy as the leading cause of blindness. Diabetic patients are prediposided to the development of glaucoma. Metabolic cataract is most commonly observed in patients with uncontrolled diabetes with high hyperglycemia.

The classical clinical features of the two main types of diabetes as regard to family history, peculiarities of symptoms, age at onset of disease are differ.



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