CURATION OF PATIENTS WITH HYPOGLYCEMIC AND HYPERGLYCEMIC COMA

Diabetes mellitus (DM) is a systemic disease that affects essentially every organ of the body. The fatal outcome is related to the development of acute or chronic complications. Classification of acute complications of DM 1. Diabetic coma: 1) diabetic ketoacidisis (DKA); 2) nonketonic hyperglycemic-hyperosmolar coma (NKHHC); 3) Lactoacidosis (LA). 2. Hypoglycemic coma (HC).

DIABETIC KETOACIDISIS (DKA) Before the area of insulin therapy, ketosis was the leading cause of death of patients with DM. Since insulin deficiency worsens the clinical picture and leads to metabolic abnormalities, the complication is more common in young diabetics. Despite insulin usage, mortality remains high (6 - 10 %). DKA results from grossly deficient insulin modulation of glucose and lipid metabolism. Predisposing factors 1) newly diagnosed diabetes (presenting manifestation); 2) inadequate administration of exogenous insulin; 3) increased requirements for insulin caused by the presence of an underlying stressful condition: an intercurrent infection (pneumonia, cholecyctitis); a vascular disorder (myocardial infarction, stroke); an endocrine disorder(hyperthyroidism, pheochromocytoma); trauma; pregnancy; surgery.

Pathophysiology of DKA Insulin deficiency (absolute or relative) glucose uptake proteolysis aminoa nitrogen cides loss lipolysis free fatty glycerol acids ketogenesis ketonemia ketonuria

Muscle breakdown weight loss Weakn ess

Hyperglycemia

Gluconeogenesis + glucogenolysis

Glucosuria Osmotic diuresis Hypotonic losses Diagnostic criteria Diabetic ketosis It is status which is characterized by increased level of ketones in blood, without clinical signs of dehydration and can be corrected by diet (fat restriction) and regular insulin injection. DKA develops over a period of days or weeks. Signs and symptoms 1. Polydipsia, polyuria and weakness are the most common presenting complaints. 2. Anorexia, nausea, vomiting, and abdominal pain may be present and mimic an abdominal emergency. Electrolyte depletion

dehydration and acidosis

3. Ileus and gastric dilatation may occur and predispose to aspiration. 4. Kussmaul breathing (deep, sighing respiration) is present as respiratory compensation for the metabolic acidosis and is obvious when the pH is less than 7,1. 5. Symptoms of central-nervous-system involvement include headaches, drowsiness, lassitude, stupor and coma (only 10 % patients are unconscious). Physical examination 1. Hypothermia is common in DKA. A fever should be taken as strong evidence of infection. 2. Hyperpnoea or Kussmaul respiration are present and related to degree of acidosis, acetone may be detected on the breath (musty (fruity) odor to the breath). 3. Tachycardia frequently is present, but blood pressure is usually normal unless profound dehydration is present. 4. Poor skin turgor may be prominent depending on the degree of hydration. 5. Hyporeflexia (associated with low serum potassium) can be elicited. 6. Signs consistent with a surgical abdomen but which follow severe ketonemia can confuse the clinical picture. 7. In extreme cases of DKA one can see hypotonia, stupor, coma, incoordination of ocular movements, fixed dilated pupils, and finally death. 8. Other signs from a precipitating illness can be present. Laboratory findings 1. The hallmark of DKA is the finding of: - hyperglycemia; - ketonemia; - metabolic acidosis (plasma pH and bicarbonates are decreased. 2. A presumptive bedside diagnosis is justified if the urine is strongly positive for both glucose and ketones.

3. Different changes of electrolyte levels in the blood can be observed and does not reflect the actual total body deficits. 4. Serum amylase and transaminases can be elevated. 5. Leucocytosis occurs frequently in DKA and therefore cannot be used as a sole indication of infectious process. Types of DKA: - abdominal (diabetic pseudoperitonitis, false acute abdomen) is characterized by acute abdomen pain, dyspeptic signs with vomiting, leucocytosis and look like acute appendicitis or peritonitis; - cardiovascular type (characterized by vascular collapse, tachycardia, cyanosis, pain in the region of the heart, arterial fibrillation and is a result of decreased blood circulating volume due to the dehydration, in old patients with coronary arteries atherosclerosis); - cerebral (encephalopathic) type (can be found in old patients with cerebral vessels atherosclerosis, characterized by changing of Kussmaul breathing on superficial, absence of corneal reflexes and is a result of intoxication and brain edema); - renal (develops in patients with diabetic nephropathy and is characterized by proteinuria, hematuria, azotemia); - mixed. Differential diagnosis DKA must be distinguished from a variety of clinical conditions, particularly those in which central-nervous system function is altered and also associated with metabolic acidosis. The patients history and physical examination often are adequate diagnostic techniques. The nurse monitors for the signs and symptoms of DKA

 checks blood pressure, pulse and respirations every 15 min until stable records urine output, temperature and mental status every hour assesses central venous pressure (when central venous catheter has been placed) usually every 30 minutes Primary nursing measures are assessing the patients airway patence, level of consciousness, hydration status, status of fluid and electrolyte replacement and levels of blood glucose (laboratory or bedside glucose monitoring) results of last indicate the efficacy of insulin replacement and establish when to switch from saline to dextrosecontaining solutions After stabilization of patients condition monitoring vital signs and recording values every 4 hours is acceptable

Treatment Treatment of diabetic ketosis 1. Inhibition of ketogenesis can be achieved by exclusion of fat from diet and increasing quantity of high-calorie carbohydrates in meal. 2. Prescription only of short-acting insulin. Treatment of diabetic ketoacidosis and coma The most important factor to emphasize is the frequent monitoring of the patient both clinically and chemically. Initially, laboratory data should be obtained every 1 3 hours and less frequently once clinical improvement is noted. If the patient is in shock, stupor or coma, a nasogastric tube, especially if vomiting, and urinary catheter are recommended. Frequent assessment of potassium status is vital. A lead II electrocardiogram (ECG) can be provide a rapid assessment of hyperkalemia (peaked T waves) and hypokalemia (flat T waves and presence of U waves). Hyporeflexia and ileus are clinical indications of potassium deficiency. Careful observation of neurological status is vital to detect the infrequent but devastating presence of cerebral edema. The goals of therapy include:

1. Rehydratation. 2. Reduction of hyperglycemia. 3. Correction of: a) acid-base and b) electrolyte imbalance. 4. Investigation of precipitating factors, treatment of complications. Rehydration The average fluid deficit in adults with DKA is 3 to 5 l. A rapid infusion of 0,9 % sodium chloride (e.g., 1 l/h for the first 1 to 2 hours) is given and then reduced to about 0,5 0,3 l/h if the blood pressure is stable and the urine follow is adequate. After the initial infusion, intravenous fluid therapy must be adjusted individually on the basis of urine output, clinical assessments of hydration and circulation, determination of plasma electrolytes and glucose. When serum glucose level is about 11 13 mmol/l administration of 5 % glucose with insulin can be performed (1 to 2 unites of insulin on each 100 ml of 5 % glucose solution). The addition of glucose to the intravenous solution is necessary for correction of tissue lipolysis and acidosis. The nurse checks for clinical indicators of fluid imbalance Edema occurs with excess interstitial fluid and is not usually apparent until the interstitial volume has increased by at least 2 to 3 L. Daily weights provide a good indication of fluid volume status. One kilogram of body weight equals 1 L of fluid. Volume overload can cause an increase in blood pressure to the point of hypertension. This is true in patients with renal failure who cannot excrete the extra volume. An increased jugular venous pressure occurs with volume overload. Orthostatic hypotension is an indication of volume depletion. In volume depletion, jugular venous pulsation may not be visible at a 45-degree angle. In severe volume depletion, the jugular venous pulsation may not be visible even with the patient lying flat (Toto, 1998). Insulin treatment DKA can be treated with low dose insulin regimens. Initial intravenous administration of 10 to 14 units of short-acting insulin has to be prescribed for the patient during first hour. Continuous intravenous infusion of

insulin in a dose 0,1 unit/kg/hour in 0,9 % sodium chloride infusion has to be given after that.
This solution can be prepared in such way: 50 units of insulin have to be added to a 500 ml bottle with 0,9 % sodium chloride solution, and as a result each 10 ml of solution will contain 1 Unite of insulin.

If the glucose level does not improve (decrease on 3,3- 5,5 mmol/l) after an hour of infusion, the rate of insulin is doubled until a response is noted. But if there is a tendency for quicker decreasing the level of glucemia we have to decrease the dose of insulin in twice. When the serum glucose concentration reaches 11-13 mmol/l, insulin can be given subcutaneously (if plasma and urine persistently negative for ketones). Blood glucose level should be maintained at about 11 mmol/l during intravenous therapy. Improvement usually is noted in 8 24 hours. Following stabilization of the clinical condition, patients are placed in insulin regimen consisting of five injections of regular insulin. Treatment of electrolyte disorders Potassium should never be given until the state of renal function is known and until the serum potassium concentration is available. In most patients the initial serum potassium is high, normal or elevated, and the initiation of potassium replacement usually can be given in 2 hours after beginning of rehydration and insulin therapy, using hourly serum measurements as a guide (table 1). Hypokalemia can lead to the disturbances of heart rhythm, weakness and paralyses of intercostal muscles, atone of stomach and intestine, development of hypakalemic coma. Table 1. Correction of potassium balance Serum potassium level Potassium deficiency < 3 mmol/l 3 gr. 3 4 mmol/l 2 gr. 4 5 mmol/l 1,5 gr. 5 6 mmol/l 1 gr. > 6mmol/l Potassium would to be infused during 3 5 hours. 2 % potassium solution 150 ml 100 ml 75 ml 50 ml -

Phosphate deficiency can be treated by potassium phosphate, magnesium deficiency can be treated by 10 % solution of MgSO4 prescription (6 8 ml each 3 hour under the control of blood pressure). Correction of metabolic acidosis The metabolic acidosis occurs due to insulin deficiency and dehydration. So ketone bodies are themselves metabolized to bicarbonate once proper therapy is begun (fluids, electrolytes, insulin) and exogenous administration of bicarbonate can overcorrect to alkalosis. The use of bicarbonate can be recommended only in the following cases: - if life-threatening hyperkalemia; - when severe lactic acidosis complicates DKA; - with severe acidosis (pH<7), especially when complicated by shock that is not responsive to appropriate fluid resuscitative measures in an attempt to improve cardiac output. Bicarbonate would be to infuse at a rate of 100 to 300 ml of 2,5 % solution. Prevention of hypokalemia can be made by intravenous droply infusion of 50 75 ml 2% potassium chloride solution on each 100 mmol of bicarbonate. Other therapeutic consideration: - since infection is one of the leading precipitating events of DKA, it should be looked for and, if found, treated appropriately; - vascular thrombosis (it is secondary to severe dehydration, high serum viscosity, and low cardiac output) heparin (5000 unites 4 times a day); - vascular collapse can be treated by mesatone (1 2 ml); glucocorticoides (dexametasone 4 mg two times a day). You must remember that development of vascular collapse after initiation of therapy should suggest the presence of gramnegative sepsis or silent myocardial infarction; - cerebral edema (It is a rare and frequently fatal complication. Some physicians believe that rapid osmotic reduction of plasma glucose should be avoided to minimize rapid osmotic changes. Some patients have premonitory symptoms (e.g., sudden headache, rapid decrease in the level of consciousness), but in others acute respiratory arrest is the initial manifestation. If cerebral edema is diagnosed,

therapeutic maneuvers might include the use of : mannitol (1 2 g/kg intravenous over 20 min), dexametasone (0,25 0,50 mg/kg/day divided q 4 6 h). But they are usually ineffective after the onset of respiratory arrest. Patients education Investigation of the factors leading to DKA helps the nurse plan specific educational efforts. The nurse teaches the patient to perform self-monitoring of blood glucose levels (SMBG) every 4 to 6 hours as long as symptoms such as anorexia, nausea, and vomiting are present and as long as SMBG results are greater than 250 mg/dL (13.8 mmol/L). The patient have to check urine ketone levels when blood glucose levels exceed 300 mg/dL (> 16.7 mmol/L). The patient have to be taught by nurse to minimize the risk for dehydration by maintaining food and fluid intake. When nausea is present, the patient is instructed to take liquids containing both glucose and electrolytes (e.g., soda pop, diluted fruit juice, and sports drinks). Small amounts of fluid may be tolerated even when vomiting is present. The patient should take 8 to 12 ounces (240 to 360 mL) of calorie-free and caffeine-free liquids every hour while awake. Liquids containing carbohydrate can be taken when the diabetic is unable to eat solid food. The risk of starvation ketosis is reduced by a minimum daily carbohydrate intake of 150 g. After consulting with the primary care provider, the nurse may instruct the patient to take additional rapid-acting (lispro) or short-acting (regular) insulin on the basis of SMBG results. NONKETONIC HYPERGLYCEMIC-HYPEROSMOLAR COMA (NKHHC OR HNC) HNC is a syndrome characterized by impaired consciousness, sometimes accompanied by seizures, extreme dehydration, , and extreme hyperglycemia that is not accompanied by ketoacidosis.

The syndrome usually occurs in patients with type 2 DM, who are treated with a diet or oral hypoglycemic agents, sometimes it is a complication of previously undiagnosed or medically neglected DM (type 2). In contrast to ketoacidosis, mortality in patients with HNC has been very high (50 %) in most series. Mortality has been associated with convulsions, deep vein thrombosis, pulmonary embolus, pancreatitis and renal failure. Death is usually due to an associated severe medical condition and not to the hyperosmolality. The pathophysiology of HNC is similar to that of ketoacidosis, except that ketoacids do not accumulate in the blood. The reason of this phenomenon is unclear. Initially it was thought that patients with HNC produced enough insulin to prevent lipolysis and ketogenesis but not enough to prevent hyperglycemia. The concept was invalidated by finding similar inappropriately low plasma insulin concentrations in patients with the two syndromes. The finding of lower plasma free fatty acids, as well as cortisol and growth-hormone concentrations, in patients with ketoacidosis has raised the possibility that the absence of ketosis may be the result of decreased cortisol and growth-hormone effects on lipolysis. Suppression of lipolysis by hyperosmolality also has been proposed. HNC usually develops after a period of symptomatic hyperglycemia in which fluid intake is inadequate to prevent extreme dehydration from the hyperglycemiainduced osmotic diuresis. Predisposing factors 1. HNC seems to occur spontaneously in about 5 7 % of patients. 2. In 90 % of patients some degree of renal insufficiency seems to coexist. 3. Infection (e.g., pneumonia, urinary tract infection, gram-negative sepsis) is underlying frequent precipitating cause. 4. Use of certain drugs has been associated with this condition: - steroids increase glucogenesis and antagonize the action of insulin; - potassium-wasting diuretics (hypokalemia decreases insulin secretion), e.g., thiazides, furosemide; - other drugs, e.g., propranolol, azathioprine, diazoxide.

5. Other medical conditions such as cerebrovascular accident, subdural hematoma, acute pancreatitis, and severe burns have been associated with HNC. 6. Use of concentrated glucose solutions, such as used in peripheral

hyperalimentation or renal dialysis, has been associated with HNC. 7. HNC can be induced by peritoneal or hemodialysis, tube feeding. 8. Endocrine disorders such as acromegaly, Cushing disease, and thyrotoxicosis have also been associated with HNC. Diagnostic criteria Signs and symptoms 1. Polyuria, polydipsia, weight loss, weakness and progressive changes in state of consciousness from mental cloudiness to coma (present in 50 % of patients) occur over a number of days to weeks. 2. Because other underlying conditions (such as cerebrovascular accident and subdural hematoma) can coexist, other causes of coma should be kept in mind, especially in the elderly. 3. Seizures occur in 5 % of patients and may be either focal or generalized. Physical examination 1. Severe dehydration is invariably present. 2. Various neurologic deficits (such as coma, transient hemiparesis, hyperreflexia, and generalized areflexia) are commonly present. Altered states of consciousness from lethargy to coma are observed. 3. Findings associated with coexisting medical problems (e.g., renal disease, cardiovascular disease) may be evident. Laboratory findings 1. Extreme hyperglycemia (blood glucose levels from 30 mmoll/l and over are common. 2. A markedly elevated serum osmolality is present, usually in excess of 350 mOsm/l. (Normal = 290 mOsm/l). The osmolality can be calculated by the following formula: mOsm/l = 2(Na + K) = blood glucose/18 + BUN/2.8. 3. The initial plasma bicarbonate averaged. 4. Serum ketones are usually not detectable, and patients are not acidic.

5. Serum sodium may be high (if severe degree of dehydration is present), normal, or high (when the marked shift of water from the intracellular to the extracellular space due to the marked hyperglycemia is present). 6. Serum potassium levels may be high (secondary to the effects of hyperosmolality as it draws potassium from the cells), normal, or low (from marked urinary losses from the osmotic diuresis). But potassium deficiency exists. Treatment This condition is a medical emergency and the patient should be placed in an intensive care unit. Many of the management techniques recommended for a patient with DKA are applicable here as well. The goals of therapy include: - rehydration; - reduction of hyperglycemia; - electrolytes replacement; - investigation of precipitating factors, treatment of complications. Rehydration The average fluid deficit is 10 liters, and acute circulatory collapse is a common terminal event in HNC. The immediate aims of treatment are to rapidly expand the contracted intravascular volume in order to stabilize the blood pressure, improve the circulation, and improve the rate of urine production.
It is important to remember that it is the severe hyperglycemia and the concomitant obligatory shift of water from the intracellular to the intravascular compartment that prevents this latter space from collapsing at the time of severe fluid depletion. With too rapid a correction of hyperglycemia, potential hypovolimic shock (as fluid moves from the extracellular space back into the intracellular space) may occur.

Treatment is starting by infusion 1 to 2 liters of 0,9 % sodium chloride over 1 to 2 hours; if this suffices to stabilize the blood pressure, circulation and restore good urine flow, the intravenous fluid can be changed to 0,45 % sodium chloride to provide some free water. 0,45 % sodium chloride is used at a rate of 150 to 500 ml/hour depending on the state of hydration, previous clinical response and the balance between fluid input and output. The aim of this phase of intravenous fluid

therapy is not to attempt to rapidly correct the total fluid deficit or the hyperosmolality, but rather to maintain stable circulation and renal function and to progressively replenish water and sodium at rates that do not threaten or cause acute fluid overload. Generally, half of the loss is replaced in the first 12 hours and the rest in the subsequent 24 hours. Insulin therapy Insulin treatment in HNC is started by 10 to 20 unites of regular insulin intravenously as a bolus dose prior to starting the insulin infusion and then giving intravenously regular insulin in a dose of 0,05 0,10 unites/kg/hour (many authorities routinely use the same insulin treatment regimens as for treating DKA, other authorities recommend smaller doses of insulin, because they believe that patients with type 2 DM are offer very sensitive to insulin, but this view is not universally accepted, and many obese type 2 diabetics with NHC require larger insulin doses to induce a progressive decrease in their marked hyperglycemia.
It is important to remember that because of insulin therapy causes blood glucose levels to fall, water shifts into the cells and existing hypotension and oliguria can further aggravated. Thus, initially some advocate delaying insulin therapy while infusion normal saline until vital signs have improved.

When the plasma glucose reaches the range 11 13 mmoll/l, 5 % glucose should be added to the intravenous fluids to avoid the risk of hypoglycemia. Following recovery the acute episode, patients are usually switched to adjusted doses of subcutaneous regular insulin at 4 to 6-hour intervals. When they are able to eat, this is changed to a 1 or 2 injection regimen. Treatment of electrolyte disorders Once urine flow has been reestablished, potassium should be added to begin repletion of the total body deficits. Potassium replacement is usually started by adding 20 mmoll/l to the initial liter of the intravenously-infused 0,45 % sodium chloride with careful serum potassium and ECG monitoring.

LACTIC ACIDOSIS (LA) DM is one of the major causes of LA, a serious condition characterized by excessive accumulation of lactic acid and metabolic acidosis. The hallmark of LA is the presence of tissue hypoxemia, which leads to enhanced anaerobic glycolysis and to increased lactic acid formation. Pyruvic acid NADH Acetoacetic Lactic acid NAD Beta-hydroxybutyric

Piruvic acid is converted into lactic acid by lactic dehydrogenase (LDH) in the presence of reduced nicotinamide adenine dinucleotide (NADH), which, in turn, is converted into NAD. The reaction is reversible and involves LDH in both directions. The conversion of acetoacetic acid into beta-hydroxybutyric acid also requires the oxydation of NADH. LA results from decreased availability of NAD caused by lack of oxygen. Likewise, the deficiency of NAD impairs the conversion of beta-hydroxybutyric into acetoacetic acid. Thus, LA predisposes to accumulation of beta-hydroxybutyric acid, which does not react with acetest tablet, so, the reaction for ketone bodies may be negative or slightly positive. The normal blood lactic acid concentration is 1mmol/l, and the pyruvic to lactic ratio is 10:1. An increase in lactic acid without concomitant rise in pyruvate leads to LA of clinical importance. Predisposing factors 1. Heart and pulmonary failure (which leads to hypoxia). 2. Usage of bigyanids, pheformin therapy. 3. Alcohol intoxication. 4. Ketoacidosis (it is important to have a very high index of suspection with respect to presence of LA). Diagnostic criteria

Signs and symptoms 1. Kussmaul breathing (deep, sighing respiration) is present as respiratory compensation for the metabolic acidosis and is obvious when the pH is less than 7.2. 2. Symptoms of central-nervous-system involvement include headaches, drowsiness, lassitude. 3. Anorexia, nausea, vomiting, and abdominal pain may be present. 4. Myalgia is common. Physical examination 1. Acrocyanosis is common. 2. Tachycardia frequently is present, blood pressure is decreased. 3. Poor skin tugor and dry skin may be prominent. 4. Hypothermia is common in LA. 5. Hyperpnea or Kussmaul respiration are present and related to degree of acidosis. 4. Findings associated with coexisting medical problems (e.g., renal disease, cardiovascular disease) may be evident. Laboratory findings 1. Blood glucose level is not high 2. Glucosurea is absent. 3. Blood lactic acid is high. Treatment of LA LA is treated by correcting the underlying cause. In severe cases, bicarbonate therapy should be used (intravenously-infused 2,5 % sodium bicarbonates 1 to 2 l/day). LA can be treated with low dose insulin regimens with 5 % glucose solution infusion. Volume expanders and oxygen therapy are helpful treatment as well. Diagnostic criteria of different hyperglycemic coma are shown in table 2. Table 2. Comparison of DCA, HNC and LA. Age Type of DM Predisposing DKA Below 40 Type 1 > type 2 Insulin deficiency HNC Above 40 Type 2 Dehydration LA Above 40 Type 2 Hypoxia

factor Prodromes

Underlying renal, cardiovascular or pulmonary disease General

Several days duration or less than 1 day About 15 %

Several days duration About 85 %

Less than 1 day

About 90 %

More acidic and less dehydrated, hyperventilation Rare

Neurologic symptoms and signs Laboratory findings - blood glucose - plasma ketones - serum sodium - serum potassium - serum bicarbonate - blood pH - serum osmolality - free fatty acids Complications: - Thrombosis - Mortality Diabetes treatment after recovery

More dehydrated and less acidic, no hyperventilation Very common

More acidic and less dehydrated, hyperventilation Very common

High (about 20 30 mmoll/l) + Normal, elevated or low Normal, elevated or low Low Less than 7,35 Less than 330 mOsm/l Rare 1 10 % Always insulin

Very high (about 40 50 mmoll/l) Normal, elevated or low Normal, elevated or low Normal Normal Over 350 mOsm/l or normal Frequent 20 50 % Diet alone or oral agents, sometimes insulin

Normal or about 10 11 mmoll/l Normal Normal Low Less than 7,35 Normal Normal Very rare About 90 % Diet alone or oral agents, sometimes insulin

HYPOGLYCEMIA It is a syndrome characterized by symptoms of sympathetic nervous system stimulation or central nervous system dysfunction that are provoked by an abnormally low plasma glucose level. Hypoglycemia represents insulin excess and it can occur at any time. Precipitating factors

- irregular ingestion of food; - extreme activity; - alcohol ingestion; - drug interaction; - liver or renal disease; - hypopituitarism and adrenal insufficiency. Diagnostic criteria Signs and symptoms Two distinct patterns are distinguished: 1) adrenergic symptoms (they are attributed to increased sympathetic activity and epinephrine release): - sweating, - nervousness,

- tremulousness, - faintness, - palpitation,

- and sometimes hunger; 2) cerebral nervous system manifestations: confusion, inappropriate behavior (which can be mistaken for inebriation); visual disturbances, stupor, coma or seizures. (Improvement in the cerebral nervous system manifestations will be with a rise in blood glucose.) A common symptom of hypoglycemia is the early morning headache, which is usually present when the patient awakes.

Patients should be familiar with the symptoms of the hypoglycemia but some of them are not heralded by symptoms. Physical examination 1. The skin is cold, moist. 2. Hyperreflexia can be elicited. 3. Hypoglycemic coma is commonly associated with abnormally low body temperature 4. Patient may be unconsciousness.

Laboratory findings 1. Low level of blood glucose Treatment Insulintreated patients are advised to carry sugar lumps, candy, or glucose tablets at all time.

If the symptoms of hypoglycemia develop, the patients have to drink a glass of fruit juice or water with 3 tbsp. of table sugar added or to eat candy, and to teach their family members to give such treatment if they suddenly exhibit confusion or inappropriate behavior: 1) glucagon 0,5 1 unit (0,5 1 ml) s/c, i/m or i/v with next fruit juice or candy taken. If the patient does not respond to 1 unit of glucagon within 25 minutes, further injections are unlikely to be effective, and are not recommended;

Glucagon 2) an i/v injection of 20 or 100 ml of 40 % glucose, followed by a continuous infusion of 5 % glucose (10 % glucose may be needed) until it clearly can be stopped safely; 3) glucocorticoids and adrenaline are helpful as well.

We recommended you to repeat general information about diabetes mellitus. Anatomy and physiology of pancreatic gland Pancreatic gland is located in the upper abdomen, with the head lying immediately adjacent to the end the body and tail extending across the midline nearly to the spleen. In adults, most of the pancreatic tissue is devoted to exocrine function, in which digestive enzymes are secreted via the pancreatic ducts into the duodenum. The endocrine pancreas consists of the islets of Langerhans (named for the 19thcentury German pathologist Paul Langerhans). There are approximately one million islets that weigh about 1 gram Approximately 75% of the cells in each islet are insulin-producing beta cells, which are clustered centrally in the islet. The remainder of each islet consists of alpha, delta, and F (or PP) cells (table 1) and are located at the periphery of the islet. Each islet is supplied by one or two very small arteries (arterioles) that branch into numerous capillaries. These capillaries emerge and coalesce into small veins outside the islet. The islets also contain many nerve endings (predominantly involuntary, or autonomic, nerves that monitor and control internal organs). Table 1. Production of hormones by pancreatic glands Cell type Endocrine product Alpha cells (A cells) glucagon Beta cells (B cells) insulin Delta cells (D cells) somatostatin F (or PP) cells pancreatic polypeptide Insulin is an anabolic hormone (promotes the synthesis of carbohydrates, proteins, lipids and nucleic acids (table 2)). The most important target organs for insulin action are: the liver, muscles and adipocytes. The brain and blood cells are unresponsive to insulin. Table 2. Biological effects of insulin Type of metabolism carbohydrate metabolism The effects of insulin stimulation of glucose transport across muscle and adipose cell membranes regulation of hepatic glycogen synthesis inhibition of glucose formation from glycogen (glycogenolysis) and from amino-acid precursors (glyconeogenesis)

Protein metabolism

Lipid metabolism

Nucleic acids metabolism Other effects of insulin:

The result of these actions is a reduction in blood glucose concentration the transfer of amino acids across plasma membranes stimulation of protein synthesis inhibition of proteolysis incorporation of fatty acids from circulating triglyceride into adipose triglyceride stimulation of lipid synthesis inhibition of lipolisis stimulation of nucleic acid synthesis by stimulating the formation of adenosine triphosphate (ATP), DNA and RNF

1) stimulation of the intracellular flew of potassium, phosphate and magnesium in the heart; 2) inhibition of inotropic and chronotropic action (unrelated to hypoglycemia). The action of insulin can be decreased by contra-insulin hormones (table 3). Table 3. Action of contra-insulin hormones Hormone glucagon somatostatin glucocorticoids Action stimulates glycogenolysis stimulates glyconeogenesis inhibits secretion of insulin regulates glucose absorption from alimentary tract into blood decrease of glucose utilization by tissues stimulate glycogenolysis stimulate glyconeogenesis increase lipogenesis (in patients with insulin resistance) inhibits -cells secretion stimulates glycogenolysis stimulates ACTH secretion stimulates -cells (which secret glucagon) increases activity of enzymes which destroy the insulin stimulates glyconeogenesis increases of glucose exit from the liver veins into blood decreases of glucose utilization by tissues stimulates glucocorticoides secretion and -cells secretion increase glucose absorption into blood stimulate glycogenolysis inhibit fat formation from the carbohydrates DIABETES MELLITUS

catecholamines

somatotropin

ACTH thyroid hormones

Epidemiology. It is probably fair to state that about 4 to 7 percentage of the world population is affected with diabetes mellitus (DM). The disease is more common in persons after age 45, in obese individuals, in certain ethnic groups, and in those with a positive family history of DM: for a child, born from the mother with type 1 diabetes, risk to get diabetes is 1:50, and from the sick father 1:15. Each 12-15 years the quantity of diabetics increases twice. The term diabetes mellitus refers to the excretion of large quantities of sweet urine. Diabetes is an old word for siphon and means dieresis, mellitus means sweet. The clinical syndrome known as DM comprises a wide variety of symptoms, physical findings and laboratory abnormalities, in which multiple etiologic factors are involved, the pathophysiology is partly understood and treatment is unsatisfactory. The hallmark of DM is hyperglycemia. Diabetes mellitus is an endocrine metabolic disease, which develops due to absolute or relative insulin insufficiency and characterized by chronic hyperglycemia, changes of different systems and organs of patient. Absolute insulin insufficiency means that pancreas produce insulin in very low quantities or doesnt produce it at all (due to destruction of beta-cells by inflammation, autoimmune process or surgery). Relative insulin insufficiency means that pancreas produces or can produce insulin but it doesnt work. (The pathologic process can be on the next levels: beta cells: they can be not sensitive for the high level of glycemia; insulin: abnormal insulin, insulin antibodies, excessive quantity of contra-insulin hormones, absence of enzyme, which converts proinsulin into insulin, etc; receptors: decreased quantity of receptors or diminished binding of insulin. Stages of diabetes mellitus development 1. Prediabetes (risk factors or predispose factors): obesity;

 positive family history of DM; persons which were born with weight more than 4,0 kg; women in which: = were born children with weight more than 4,0 kg; =had abortions and dead child in anamnesis; - persons with: = atherosclerosis, hypertension; = autoimmune diseases; = furunculous; = rubella, mumps, Coxsackie virus, infectious hepatitis, cytomegalovirus, infection mononucleosis. 2. Impaired glucose tolerance (latent DM). 3. Clinical manifestation of DM. Etiologic classification of DM (WHO recommendations, 1999) I. Type 1* of DM (destruction of -cells which mostly leads to absolute insulin insufficiency): autoimmune; idiopathic.

II.

Type 2 of DM (resistance to insulin and relative insulin insufficiency or defect of insulin secretion with or without resistance to insulin).

III.

Other specific types: genetic defects of -cells function (MODY-1; MODY-2; MODY-3; etc); genetic defects of insulin action (insulin type A resistance, lipoatrophic diabetes, Rabson-Mendenchole syndrome, leprechaunism, etc); diseases of the exocrine pancreas (pancreatitis; trauma, pancreatectomy; neoplasia; cystic fibrosis, fibrocalculosis; hemochromatosis); endocrinopathies (acromegaly; Cushings syndrome; pheochromocytoma; glucagonoma, thyrotoxicosis, aldosteroma, somatostatinoma) drugor chemical-induced (Vacor**; Pentamidine; Nicotinic acid;

Glucocorticoids; Thyroid hormone; Diazoxide; Beta-adrenergic agonists; Thiazides; Phenytoin; Alfa-interferon); infections (Congenital rubella; Cytomegalovirus) Uncommon forms of immune-mediated diabetes (stiff-man, antibodies for insulin, antibodies for insulin receptors) Other genetic syndromes sometimes associated with diabetes (Down syndrome; Klinefelter's syndrome; Turner's syndrome; Wolfram syndrome; Friedreich's ataxia; Huntington's chorea; Lawrence-Moon Beidel syndrome; Myotonic dystrophy; Porphyria; Prader-Willi syndrome; etc) IV. Gestation diabetes.
*- Arabic numerals are specifically used in the new system to minimize the occasional confusion of type II as the number 11 **- Vacor is an acute rodenticide that was released in 1975 but withdrawn as a general-use pesticide in 1979 because of severe toxicity. Exposure produces destruction of the beta cells of the pancreas, causing diabetes mellitus in survivors.

Type 1 is characterized by pancreatic islet beta cell destruction and absolute insulinopenia. Current formulation of the pathogenesis of type 1 DM includes the following: 1. A genetic predisposition, conferred by diabetogenic genes on the short arm of chromosome C, either as part of it or in close proximity to the major histocompatibility complex (MMHC) region (more than 95 % of type 1 diabetes

individuals are HLA DR3, DR4 or DR3/DR4; on the other hand, HLA DR2 confers protection against the development of type 1 DM); 2. Putative environmental triggers (possibly viral infections (Coxsackie B, rubella) or chemical toxins (nitrosourea compounds)) that in genetically susceptible individuals might play a role in initiating the disease process. 3. An immune mechanism gone awry, either initiation of immune destruction or loss of tolerance, leading to slow, progressive loss of pancreatic islet beta cells and eventual clinical onset of type 1 diabetes. Stages of type 1 DM development (by Flier, 1986) I. II. III. IV. V. VI. A genetic predisposition or changes of immunity. Putative environmental triggers. Active autoimmune insulities with -cells destruction. Progression of autoimmune insulities with destruction of >50 % of -cells. Development of manifest DM (table 1). Total -cells destruction. Pathophysiology of DM Defective polymorphonuclear function infection Hyperglycemia glucosurea polyurea dehydration Insulin lack Hyperosmolality Proteolysis weight loss muscle wasting polyphagia Lipolysis free fatty acid release ketosis acidosis Table 1. The classic manifestation of diabetes mellitus Signs and symptoms Polyurea Mechanism of their development - once plasma glucose concentration exceeds the renal threshold (about 180 ml/dl or 8 9 mmol/l) glucosurea ensues. Osmotic diuresis induced by glucose results in polyurea and subsequent polydipsia; - as more water is excreted, the body requires more water intake; - this occurs to lack of energy; - energy (calories) is lost as glucose in the urine. Loss of water itself also contributes to weight loss. Increased proteolysis with

Polydipsia Polyphagia loss of weight

mobilization of aminoacids leads to enhancement of protein catabolism and loss of weight, notably in muscle mass; fatigue and - probably occur as a result of decreased glucose utilization and electrolyte abnormalities; weakness - develops due to increased lipolysis which cause the release of acidosis free fatty acids, which are metabolized to ketones by the liver. Individuals with type 1 DM are ketosis prone under basal conditions. The onset of the disease is generally in youth, but it can occur at any age. Patients have dependence on daily insulin administration for survival. Type 2 DM is the most common form of diabetes, accounting for 95 90 % of the diabetic population. Most investigators agree that genetic factors underlie 2 DM, but it is probably not caused by defects at a single gene locus. Obesity, diet, physical activity, intrauterine environment, and stress are among the most commonly implicated environmental factors which play a role in the development of the disease. Presenting signs and symptoms of type 2 DM include polyurea, polydipsia, polyphagia; the majority of individuals (80 85 %) are obese, but it can also occur in lean persons. Patients with DM are at risk of chronic complications developing (Chapter ???? tablers???). Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.

Physical examination Skin The skin is a common target of DM. Many lesions can be observed, but none is specific to the disease, with the possible exception of necrobiosis lipoidica diabeticorum (it consists of skin necrosis with lipid infiltration and is also characteristically found in the pretibial area. The lesions resemble red plaques with distinct borders).

The most common skin lesion is diabetic dermopathy (it is characterized by brown, atrophic, well-demarcated areas in the pretibial region which resemble sears), besides patients sometimes have xanthoma diabeticorum, which is usually located on the buttocks, elbows and knees, look like eruptions (but is not really diabeticorum since it occurs in the patients with lipoprotein abnormalities, particularly hyperchylomicronemia, whether or not patient has DM). The skin is dry and itches. Infections of the skin by bacteria and fungi, candidiasis of the external female genitalia, hyperkeratosis, and nail disorders are common in the patients with DM but nothing is specific with regard to their development. Subcutaneous adipose tissue The abdomen type of obesity is common in patients with type 2 DM. Sometimes generalized subcutaneous adipose tissue atrophy can be observed in diabetics. Bones Osteoporosis and osteoarthropaphy can be finding in patients with DM. Gastrointestinal tract Paradontosis, gastritis with decreased secretion ability, gastroduodenitis, hepatosis and diarrhea are common in patients with DM. Cardiovascular system (CVS) Involvement of CVS, particularly the coronary circulation, is common in patients with DM. The heart, arteries, arterioles, and capillaries can be affected. Cardiovascular changes tend to occur earlier in patients with DM when compared with individuals of the same age, in the same quantity cases in both sexes. Atypical (painless) forms of ischemic heart disease are common in diabetics. Several factors play a role in the high incidence of coronary artery disease seen in patients with DM. These include age of the patient, duration and severity of the diabetes, and presence of other risk factors such as hypertension, smoking and hyperlipoproteinemia. It has been suggested that in some patients with DM, involvement of the small vessels of the heart can lead to cardiomyopathy, independent of narrowing of the major coronary arteries. Myocardial infarction is responsible for at least half of deaths in diabetic

patients, and mortality rate for the diabetics is higher than that for nondiabetics of the same age who develop this complication. Hypertension is common in patients with DM, particularly in the presence of renal disease (as a result of atherosclerosis, destruction of juxtaglomerular cells, sympathetic-nervous-system dysfunction and volume expansion). Atherosclerosis of femoral, popliteal and calf larger arteries may lead to the diabetic macroangiopathy of lower extremities, which presents as intermittent claudication, cold extremities, numbness, tingling and gangrene. Diabetic microangiopathy of lower extremities can be on patients also.

Respiratory system Mucomycosis of the nasopharinx, sinusitis, bronchitis, pneumonia, tuberculosis are more common in patients with diabetes than in nondiabetics. Kidneys and urinary tract Renal disease include diabetic nephropathy, necrosing renal papillitis, acute tubular necrosis, lupus erythematosus, acute poststreptococcal and

membranoproliferative glomerulonephritis, focal glomerulosclerosis, idiopathic membranous nephropathy, nonspecific immune complex glomerulonephrities, pyelitis, pyelonephritis, cystitis and others. Obviously, these abnormalities, with exception of diabetic nephropathy, are not at all peculiar to DM and can be observed in many other conditions. Diabetic nephropathy can develop in patients with DM. Eyes Complications of the eyes include: diabetic retinopathy ceratities, retinitis, chorioretinitis, and cataracts. The last one occurs commonly in the patients with longstanding DM and may be related to uncontrolled hyperglycemia (glucose metabolism by the lens does not require the presence of insulin. The epithelial cells of the lens contain the enzyme aldose reductase, which converts glucose into sorbitol. This sugar may be subsequently converted into fructose by sorbitol dehydrogenase. Sorbitol is retained inside the cells because of its difficulty in transversing plasma membranes. The rise in intracellular osmolality leads to increased water uptake and swelling of the lens).

The diagnosis of DM The diagnosis of DM may be straightforward or very difficult. The presence of the marked hyperglycemia, glucosuria, polyuria, polydipsia, polyphagia, lethargy, a tendency to acquire infections, and physical findings consistent with the disease should offer no difficulty in arriving at the correct diagnosis. On the other hand, mild glucose intolerance in the absence of symptoms or physical findings does not necessarily indicate that DM is present. The diagnosis of DM include: 1. Clinical manifestations of DM. 2. Laboratory findings. 1) fasting serum glucose (if the value is over 6,1 mmol/l (120 mg/dl) on two or more separate days, the patient probably has DM); 2) the glucose tolerance test (GTT): If the diagnosis is still in doubt, then perform a GTT (table 2). Conditions for performing an oral GTT have been standardized: no special dietary preparation is required for an oral GTT unless the patient has been ingesting <150 gm/day of carbohydrate. Then give 150 200 gm carbohydrate daily for 3 days prior to test; unrestricted physical activity should proceed the test; test is performed in the morning, following overnight fast of 10 to 16 hours; subjects should remain seated, without prior coffee or smoking; blood for glucose determination is obtained from an anterior cubital vein before glucose ingestion and in 2 hours after ingestion; the amount of glucose given is 75 g for adults (100 g pregnant women, and 1,75 g/kg of ideal body weight for children). Patient have to drink glucose dissolved in 250 ml of water. Table 2. Interpretation of glucose tolerance test results Diagnosis Normal Impaired fast glycemia Impaired glucose tolerance Diabetes mellitus (table 3) The level of capillary blood glucose, mmol/l Fast 2 hours after glucose intake 3,3 5,5 <7,8 5,5 6,1 <7,8 5,5 6,1 7,8 11,1 >6,1 >11,1

The major indication for an oral GTT is to exclude or diagnose DM (mostly type 2) in those suspected of having diabetes although fasting or symptomatic hyperglycemia is absent; e.g., in patients with a clinical condition that might be related to undiagnosed DM (e.g., polyneuropathy, retinopathy). Various conditions (other than DM) and drugs can cause abnormalities in the oral GTT. The criteria of DM do not apply to patients treated with drugs that can impair glucose tolerance (e.g., thiazids, glucocorticoids, indometacin, nicotinic acid, oral contraceptives containing synthetic estrogenes) or to patients who develop nausea, sweating, faintness or pallor during the test, or to have infections, hepatic, renal and endocrine disease that impairs glucose tolerance. 3) glycohemoglobin (HbA1c) (This test is an indicator of blood sugar control during the previous 2-to-3-month period. The level of HbA1c >6,5% estimate diagnosis of DM and may be alternative method of DM diagnostic criteria in compare to GGT); 4) islet cell antibody levels will be positive prior to any insulin administration in 60 80 % of patients with type 1 DM; 5) C-peptide (it is not affected by antibodies to exogenous insulin and is used to distinguish type 1 and 2 DM if there is still a need after clinical determination); 6) glucose level in urine; 7) acetonurea; 8) blood lipids and others. 3. Instrumental investigations usually are used to diagnose chronic complications of DM.

Table 3. Differential diagnosis of type 1 and type 2 DM Signs 1. 2. 3. 4. 5. 6. Age Beginning of disease Duration Ketosis, ketoacidosis Body weight Treatment Type 1 DM Young (under 40) Acute Labile Often develops Decreased or normal Insulin, diet Type 2 DM Old, moderate (over 40) Gradual Stable Rare develops Obesity in 80-90%of patients Diet, oral hypoglycemic

agents or insulin 7. Degrees of severity (table 4) 8. Season of disease beginning 9. Connection with HBAsystem 10. Level of insulin and Cpeptide 11. Antibodies to -cells 12. Late complications 13. Mortality 14. Spreading Moderate, severe Frequently autumn-winter period Present Decreased or absent Present in 80-90% of patients on first year Microangiopathies Less than 10% 10-20% Mild, moderate, severe Absent Absent Frequently normal level Absent Macroangiopathies More than 20% 80-90%

Table 4. Degrees of severity of DM Criteria compensation can be achieved by mild Diet Degree of severity moderate oral hypoglycemic agents (in patients with type 2 DM) or insulin (in patients with type 1 DM) 8,4 14,0 20 to 40 gr. /l (2 4 %) ketosis can occur Severe by insulin or oral hypoglycemic agents

fast serum glucose level, mmol/l Glucosuria Complications Acute complications

8,4 20 gr. /l (2 %)

14,0 40 gr. /l (4 %)

ketosis is common, frequent hypoglycemia complications can be last stages of longobserved (but not last term (chronic) stages*) complications are present** * - nonproliferative stage of diabetic retinopathy, diabetic nephropathy on stage of microalbuminurea, diabetic neuropathy, etc; ** - preproliferative or proliferative stages of diabetic retinopathy, diabetic nephropathy on stage of proteinurea or chronic renal failure, autonomic diabetic neuropathy, diabetic foot syndrome, postinfarction cardiosclerosis, stroke, etc. Stages of compensations:

proneness to ketosis does not occur long-term are rare or only (chronic) functional stages complications can be observed

1. Compensation. 2. Subcompensation. 3. Decompensation. Criteria of compensative stage 1. Patient hasnt new complains. 2. Fast serum glucose level is normal (but can be under 7.0 mmol/l in old patients or which have cardiovascular disorders) (table 5). 3. Glucose in urine is absent. 4. Glucose level fluctuation is under 4.4-5.5 mmol/l during the day . 5. HbA1c <7,0% 6. Comatose and precomatose statuses are absent. Criteria of subcompensative stage 1. Patient may have new complains. 2. Fast serum glucose is high. 3. Glucosuria is present. 4. Glucose level fluctuation is over 4.4-5.5 mmol/l during the day. 5. HbA1c 7,1 7,5%. 6. Comatose or precomatose statuses are absent. Table 5. Criteria of carbohydrate metabolism compensation in patients with DM Criteria compensation subcompensation HBA1c, % <7,0 7,1 7,5 Fast glucemia* 5,0 6,0 6,1 6,5 Postprandial glucemia (in 2 7,5 8,0 8,1 9,0 hours after meal intake) Glucemia at bedtime 6,0 7,0 7,1 7,5 *The level of glucose in capillary blood, mmol/l **Criteria of decompensate stage: 1. Comatose or precomatose status are present. Duration of DM 1. Stabile (glucose level fluctuation is under 4.4-5.5 mmol/l during the day and comatose or precomatose status are absent). decompensation ** >7,5 >6,5 >9,0 >7,5

2. Labile (glucose level fluctuation is over 4.4-5.5 mmol/l during the day or comatose and precomatose status are present). Mechanism of formulation of diagnosis is shown in table 6. Table 6. Formulation of diagnosis Disease Peculiarity type or as a result of degree of severity Type, stage or degree -1 -2 - or to show a cause (in a case of another types of DM) - mild - moderate - severe - compensation - subcompensation - decompensation - nephropathy (stage) - retinopathy (stage on each eye) - angiopathy of lower extremities (stage) - peripheral - autonomic (type) - central - ischemic heart disease (type) - heart failure (stage according NYHA) - angiopathy of lower extremities (stage) - ischemic - neuropathic - mixed degree in a case of presence

stage

Diabetes mellitus

diabetic microangiopathy

diabetic neuropathy

diabetic macroangiopathy

syndrome of diabetic foot

arterial hypertension dyslipidemia concomitant diseases Example of diagnosis. Diabetes mellitus type 1, severe degree, stage of subcompensation. Diabetic peripheral neuropathy. Diabetic preproliferative retinopathy. Diabetic nephropathy IV stage. Secondary arterial hypertension, II stage, moderate degree. Chronic (long term) complications The long-term degenerative changes in the blood, vessels, the heart, the kidneys, the nervous system, and the eyes as responsible for the most of the morbidity and mortality of DM. There is a causal relationship and the level of the metabolic control. Classification of chronic (long-term) complications of DM I. Diabetic angiopathy: 1. Microangiopathy:

1) retinopathy; 2) nephropathy; 3) angiopathy of lower extremities. 2. Macroangiopathy: 1) ischemic heart disease; 2) angiopathy of lower extremities. II. Diabetic neuropathy. 1) peripheral; 2) visceral (autonomic); 3) central. Diabetic retinopathy Dibetics need careful ophthalmologic examination (at least yearly) by ophthalmologist experienced with diabetes. Background retinopathy (the initial retinal changes seen on the

ophthalmoloscopic examination) does not significantly alter vision, but it can lead to processes that cause blindness (e.g., macular edema or proliferative retinopathy with retinal detachment or hemorrhage. Evidence of retinopathy, rarely present at diagnosis in type 1 DM, is present in up to 20 % of type 2 DM patients at diagnosis. About 85 % of all diabetics eventually develop some degree of retinopathy.

Diabetic retinopathy is classified according to the changes seen at background during ophthalmoscope examination with pupils dilated (Table 1). Table 1. Classification of diabetic retinopathy Stage of diabetic Type Characteristic of changes

retinopathy Nonproliferative (background) retinopathy - vascular - exudative - hemorrhagic - ischemic Preproliferative retinopathy - vascular - exudative - hemorrhagic - ischemic Proliferative retinopathy - neovascular - gliose the same changes as in nonproliferative stage but large quantity of retinal hemorrhages, intraretinal microvascular abnormalities and macular edema a hallmark of this complication is neovascularization, i.e., growth of new vessels in areas of hypoperfusion. retinal microaneurysms, hard and soft exudates, small quantity of hemorrhages an ischemic zones

Adhesion of the vessels to the vitreous leads to retinal detachment, vitreous hemorrhage, secondary rubeos glaucoma, subatrophy of eyeball and others. The prognosis is extremely poor. 5 years after recognition of this complication 50 % of the patients are blind. The mechanisms involved in the development of retinopathy are not clearly known. Genetic predisposition, growth hormone, hypoxia, and metabolic abnormalities particularly of lipids, have been implicated. Treatment of diabetic retinopathy 1. Compensation of carbohydrate metabolism (HbA1C<7,0%), because there are direct relationships between stage of diabetes mellitus compensation and development of diabetic retinopathy. 2. Treatment in nonproliferative stage include: angioprotectors; anabolic agents (nerabol 5 mg, nerabolil 1mg/week 1,5 2 month, retabolil 1ml/3 weeks 3 6 times); hypocholesterol agents (lipamid, lovostatin);

 antioxydative therapy (emoxipin, trental); vitamins B ,A, E, PP; anticoagulants. 3. Laser photocoagulation (local, focal, panretinal), criocoagulation or vitrectomy with endolazercoagulation, which have to performed by ophthalmologist in preproliferative and proliferative stage of retinopathy. 1) nonproliferative retinopathy:

Diabetic nephropathy Diabetic neuropathy it is specific damaging of kidney vessels in diabetics and characterized by nodule or diffuse glomerulosclerosis development. It is usually asymptomatic until end stage renal disease develops, but it can course the nephrotic syndrome prior to the development of uremia. Nephropathy develops in 30 to 50 % of type 1 DM patients and in small percentage of type 2 DM patients. Arteriolar hyalinosis, a deposition of hyaline material in the lumen of the afferent and efferent glomerular arterioles, is an almost pathognomic histological lesion of DM (table 2).

Table 2. Classification of diabetic nephropathy by Mogensen Stage of diabetic nephropathy Characteristic - increased renal blood circulation; I. Hyperfunction of kidneys - increased glomerular filtration rate (GFR*) (> 140 ml/min); - hypertrophy of kidneys; - normoalbuminuria (<30 mg/day) - mesangial changes due to accumulation of immunoglobulins II. Stage of initial changes of kidney structure (IgG, IgM), complement and other nonimmunologic proteins (lipoproteins, fibrin); - high GFR; - normoalbuminuria III. Initial nephropathy - microalbuminuria (30 to 300 mg/day); - high or normal GFR;

- periods of blood hypertension IV. Nephropathy or nephrotic stage - persistent proteinurea (>500 mg/day); - normal or decreased GFR; - persistent blood hypertension - decreased GFR; V. Chronic renal failure or uremia - blood hypertension; - increased serum creatinine; - signs of intoxication *GFR - glomerular filtration rate. The GFR is the best test to measure the level of kidney function and determine your stage of kidney disease. Normal GFR varies according to age, sex, and body size, and declines with age. There are several different techniques used to calculate or estimate the glomerular filtration rate (GFR or eGFR). It can be found by Reberg Tareyev test, using Modification of Diet in Renal Disease (MDRD), Cocrofta Gaulta formula and other useful calculators http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm The severity of chronic kidney disease (CKD) is described by five stages. Normal kidney function GFR above 90mL/min/1.73m2 and no proteinuria. 1) CKD1 GFR above 90mL/min/1.73m2 with evidence of kidney damage; 2) CKD2 (Mild) GFR of 60 to 89 mL/min/1.73m2 with evidence of kidney damage; 3) CKD3 (Moderate) GFR of 30 to 59 mL/min/1.73m2; 4) CKD4 (Severe) GFR of 15 to 29 mL/min/1.73m2; 5) CKD5 Kidney failure - GFR less than 15 mL/min/1.73m2

Treatment of diabetic hephropathy Stages I-III 1. Compensation of carbohydrate metabolism (HbA1C<7,0%), because there are direct relationships between stage of diabetes mellitus compensation and development of diabetic nephropathy.

2. ACE-inhibitors or ARA in suppressive doses in patients with normal blood pressure and therapeutic while it more than 130/80 mm.Hg. (contraindicated during pregnancy). 3. Correction of dyslipedemia (while present). 4. Moderate restriction of animal protein in diet ( 1gr/1 kg of patients weight). Stage IV 1-3 - as in stage I-III. 4. Restriction of animal protein in diet ( 0,8gr/1 kg of patients weight). 5. Correction of secondary anemia. Stage V 1-5 as in stage IV. 6. Correction of electrolytes level: potassium, calcium, phosphorus. 7. Enterosorbtion. Terminal stage 1. Extracorporal renal replacement therapy: hemodialysis, peritoneal dialysis. 2. Transplantation of kidney. Indications for extracorporal renal replacement therapy: - GFR< 15 ml/min; - serum potassium > 6,5 mmol/l; - severe hyperhydration with risk of lung edema development; - increasing of protein energy insufficiency.

Diabetic angiopathy of lower extremities Atherosclerosis of large vessels (macroangiopathy) leads to intermittent claudication, cold extremities and other symptoms which can be also find while arteriols and capillaries are affected (microangiopathy (table 3)). Table 3. Classification of lower extremities angiopathy Stage I. II. Nonclinic stage Functional stage Characteistic Changes could be find only during instrumental examination It is characterized by cold extremities, numbness, tingling,

pain during physical examination III. Organic stage It is characterized by trophyc changes: dry skin, hypo- or atrophy of muscles, ulcers, gangrene

Treatment of diabetic angiopathy of lower extremities Patient have to be educated in foot care; early detection of risk factors, ulcers, infections, calluses, exposed nails, diminished pulses, deformities Medicaments therapy 1. Compensation of carbohydrate metabolism (HbA1C<7,0%). 2. Smoking. 3. Correction of hypertension. 4. Treatment of dislipidemia. 5. Decreasing of extremities ischemia: - vasodilators; - anticoagulants and antiaggregative preparations (under the control of coagulogram and retina). 6. Antibacterial therapy (in a presence of ulcers). Surgical therapy (in specialized department).

Peculiarities of ischemic heart disease in diabetics 1. Cardiovascular changes tend to occur earlier in patients with DM when compared with individuals of the same age. 2. Frequency of myocardial infarction (MI) and mortality is higher in diabetics than that in nondiabetics of the same age. 3. The prognosis is even worse if ketoacidosis, or other complications of DM are present. 4. Diabetic patients have more complications of MI (arrhythmias, cardiogenic shock and others) than nondiabetic ones. 5. Often can observe atypical forms (without pain). 6. Male: female = 1:1 (nondiabetics = 10:1).

Diabetic neuropathy It is an old clinical observation that the symptoms of neuropathic dysfunction improve with better control of DM, lending support to the idea that hyperglycemia plays an important role. Accumulation of sorbitol and fructose in the diabetic nerves leads to damage of the Schwann cells and segmental demyelization.

Classification of diabetic neuropathy I. Central neuropathy (1) encephalopathy is characterized by decreased memory, headache, inadequate actions and others; 2)myelopathy). II. Peripheral polyneuropathy (radiculoneuropathy). There are three types of radiculoneuropathy: distal polyradiculoneuropathy (It is characterized by symmetrical sensory loss, pain at night and during the rest, hyporeflexia, decreased response touch, burning of heels and soles. The skin becomes atrophic, dry and cold, hair loss may be prominent. The decreased response to touch and pain predisposes to burns and ulcers of the legs and toes.); truncal polyradiculoneuropathy (It is an asymmetric, and characterized by pain (which is worse at night), paresthesia and hyperesthesia; muscular weakness involves the muscles of the anterior thigh; reflexes are decreased; weight loss is common.); truncal monoradiculoneuropathy (It is usually involves thoracic nerves and the findings are limited to the sensory abnormalities in a radicular distribution.). III. Visceral dysfunction: 1) gastrointestinal tract: esophageal neuropathy (It is characterized by segmental distribution with low or absent resting pressure in the low or absent resting pressure in the lower esophageal sphincter and by absence of peristalsis in the body of the esophagus.); diabetic gastroparesis (It leads to the irregular food absorption and is characterized by nausea, vomiting, early satiety, bloating and abdomen pain.);

involvement of the bowel (It is characterized by diarrhea (mostly at night time, postural diarrhea), constipation, malabsorption and fecal incontinence;

2) urinary tract: neurogenic vesicle dysfunction (It is characterized by insidious onset and progression of bladder paralysis with urinary retention.); 3) sexual disorders: retrograde ejaculation (which is caused by dysfunction of the pelvic autonomic nervous system); impotence, and sometimes decreased libido;

4) cardiovascular system (diabetic cardioneuropaty): orthostatic hypotension (It is characterized by dizziness, vertigo, faintness, and syncope upon assumption of the upright posture and is caused by failure of peripheral arteriolar constriction); tachycardia (but it does not occur in response to hypotension because of sympathetic involvement). Treatment of diabetic neuropathy 1. Compensation of carbohydrate metabolism (HbA1C<7,0%). 2. Sulfate-containing preparations: - lipoid acid (dialipon, berlition, tiogamaturbo), unitiol, sodium thiosulfate, gabapentyn. 3. Vitamin B-complex. 4. Vasodilators. 5. Symptomatic therapy (, non-steroid anti-inflammatory drugs, analgetics, etc). 6. Inhibitors of aldose reductase (sorbinil), multivitamins, phenytoin,

carbamazepin (Tegretol), amitriptyline. 7. In patients with encephalopathy nootropil, piracetam have to be prescribed/ 8. Physiotherapy (inductotermia, magnitolazerotherapy and others).

Diabetic foot Appearance of diabetic foot is caused by a combination insufficiency, neuropathy, and infection. Diabetic foot is divided on three types: of vascular

- neuropathic: 1) non-ulcer changes and foot ulcer; 2) diabetic arthropathy;

- ischemic; - mixed. Neuropathic arthropathy (Charcots joints) is characterized by painless swelling of the feet without edema or signs of infection. The foot becomes shorter and wider, aversion, external rotation, and flattening of the longitudinal arch. This arthropathy is associated with sensory involvement, particularly impairment of afferent pain proprioceptive impulses. Peculiarities of diabetic foot types are shown in table 4. Table 4. Peculiarities of ischemic and neuropathic diabetic foot Sign Temperature skin Color of the skin Pulsation peripheral vessels Edema Sensibility Ulcers Gangrene Treatment absent partly decreased or normal peripheral (distant), painful dry can be present decreased or absent under the pressure, no painful moist pallor or cyanotic on decreased or absent normal or pink normal of Ischemic the decreased Neuropathic normal

look treatment of diabetic look treatment of diabetic angiopathy extremities TREATMENT OF DIABETES MELLITUS. of lower neuropathy

The treatment of patients with DM is very important and may be difficult because of problems in achieving of normal glucose control. Because there is good evidence that hyperglycemia conveys risks for all of the common long-term complications of DM, which are the major cases of excess morbidity and mortality in diabetics. The main principles of DM therapy. 1. Maintenance of metabolic status at normal level or as close to normal as possible (especially blood glucose and lipid concentration). Achievement of DM compensation. 2. Achievement and maintenance of normal or reasonable body weight. 3. Maintenance (preservation) of working capacity. 4. Prophylaxis of acute and chronic complications.

Treatment of DM has to be individualized and includes such methods: 1. Diet. 2. Oral hypoglycemic agents or insulin (indications for each vary with the type of DM and severity of the disease). 3. Exercise program. 4. Phytotherapy (plants therapy). 5. Nontraditional methods of treatment. 6. Education of the patients about the nature of the disease, the importance of its control, all aspects of self-management and routine practices to minimize the development or severity of the diabetes complications. Physician has to educate, motivate and monitor progress. Patient must understand the importance of differing life-style. Diet is the keystone of the treatment of the DM. The main principles of diet. 1. Balanced diet (diet should include physiologic meal components: carbohydrate comprises 50 60 % of total calories, fat 24 25 % and protein 16 15 %). 2. Normal-calorie diet in patients with type 1 DM (35-50 kcal/kg of ideal weight (weight = height 100)) and low-calorie diet in obese persons (mostly in patients

with type 2 DM (20 25 kcal/kg of ideal weight)). We try to decrease weight in obese patients on 1-2 kg/month by such diet. (Obesity leads to insensitivity of muscle and adipose tissue to insulin, presumable as the result of decreased binding of insulin to its plasma membrane receptor. Hyperglycemia is the face of increased insulin secretion and hyperlipoproteinemia are secondary to this abnormality. The defect in insulin binding and secretion is corrected by weight reduction.) 3. Regimen has to be consist of 4 5 6 small feedings a day. (The most frequent regimen consists of 4 feedings a day, in which breakfast comprises 30 % of total calories, dinner 40 %, lunch 10 %, supper 20 %. Sometimes patients need second breakfast (when they have a tendency to develop hypoglycemia). In such case it comprises15 % of the total calories and we decrease the quantity of calories of the first breakfast and dinner). 4. Exclusion of high-calorie carbohydrates (sugar, biscuits, white bread, alcohol). 5. Increasing the quantity of high fiber-containing foods (fruits (exclusion: banana, grapes), vegetables, cereal grains, whole grain flours, bran. Patients need 40 g fibers per day. 6. Limiting of meat fat, butter, margarine in diet, decrease red and brown meats, increase poultry and fish, encourage skim milk-based cheeses. Should be used skim or low-fat milk, not more than 2 3 eggs weekly. 7. Alcohol should be avoided as much as possible because it constitutes a source of additional calories, it may worsen hyperglycemia, and it may potentiate the hypoglycemic effects of insulin and oral hypoglycemic agents. Sometimes (mostly in obese diabetics) achievement and maintenance of normal body weight may be enough to eliminate the need for oral hypoglycemic agents or insulin. So, the diet should be planned in such way that the patient can follow it for the rest of his or her life without starving or becoming malnourished.

Oral hypoglycemic agents. Inadequate control of hyperglycemia by the diet and exercises interventions suggests the need for a good glucose-lowering agent.

Oral hypoglycemic agents are useful only in the chronic management of patients with type 2 (table 1). Table 1. Commonly used oral hypoglycemic agents Group of oral hypoglycemic agents Insulin sensitizers Insulin secretagogues Oral hypoglycemic agents Increase sensitivity of tissues biguanides to insulin thiazolidinediones sulfanilureas Stimulation of insulin secretion non-sulfanylureas insulin stimulators Incretin mimetics - mimic the exenatide natural hormones in your body liraglutide that lower blood sugar vildagliptine Incretin enhansers stimulate sitagliptine incretin hormones effects saxagliptine Inhibite gastrointestinal tract acarbose absorption Mechanism of action

Incretin modulators

Alpha-glucozidase inhibitors

Sulfanilureas (table 2) include: - first generation: Tolbutamide, Chlorpropamide, Tolazemide, Acetohexamide (now are not used in treatment of the diabetics); - second generation: Glibenclamide (Maninil (3,5 mg, 5 mg), Daonil (5 mg)), Glipizide (Glurenorm (0,03), Minidiab (5 mg)), Gliclazide (Diamicron (0,08)), Gliquidon; - third generation: Glimepiride (Amaryl (1 mg, 2 mg). Table 2. Commonly used sulphonylureas Preparation Recommended dosage, Duration of action, times/day mg hours Gliclazide 80-240 8-12 1-3 Gliclazide MR 20-120 24 1 Glipizide 2,5-3,0 16-24 1-2 Glibenclamide 2,5-20 16-24 1-2 Glimepiride 1-8 24 1 Gliquidone* 30-120 8-10 1-3 * mostly metabolized by liver (5% excreted with urine, 95%goes with bile into intestine), therefore can be used in renal failure Action:

1) influence on the pancreatic gland: - increasing of the -cells sensitivity to the glucose and as a result higher secretion of glucose; - stimulation of the exocytosis of insulin by insulocytes; 2) nonpancreatic influence: - increasing number of the receptors to insulin; - normalization of receptors sensitivity to insulin; - increasing of glucose transportation inside muscle cells; - stimulation of glycogen synthesis; - decreasing of glycogenolysis and glyconeogenesis; - decreasing of glucagon secretion and others. Indications: patients with type 2 DM (over the age of 35 50 years) who do not suffer severe metabolic abnormalities (hyperglycemia), ketosis or hyperosmolality; [duration of diabetes less than 15 years.] Contraindications: type 1 DM; blood diseases; acute infections, heart, cerebral diseases; trauma, major; pregnant diabetics or lactation; III IV stages of angiopathy (but Glurenorm can be used in patients chronic renal failure, because of gastrointestinal tract excretion); coma and precoma. Side effects: hypoglycemia (hypoglycemic effect of sulfanilureas will be the most obvious in 7 12 days from the beginning of the treatment); allergy; influence on gastrointestinal tract (nausea and others); leucopenia (decreasing of the quantity of white blood cells, platelets);

 primary or secondary failure. (Primary failure defined as an inadequate response during the first month of treatment with maximum dosage, occurs in approximately 5 % of patients. Secondary failure is defined as a recurrence of hyperglycemia after an initial satisfactory response. Secondary failure may be due to nonadherence to eihter diet or sulfanilurea therapy, to disease progression, or to loss of efficacy of the agent.)

Biguanides (table 3): Metformine (Siofor 500, 850 mg), Adebit, Bufarmin. (The usual starting dose is 500 mg 12 hourly with meal increasing gradually to max 1 g 8-hourly.) Table 3 . Commonly used biguanides Preparation metformine Action: Recommended dosage, Duration of action, times/day mg hours 500-3000 8-12 3

inhibition of gastrointestinal glucose absorption; decreasing of glyconeogenesis, lipogenesis; enhancing glucose transport into muscle cells; increasing the quantity of insulins receptors; stimulation of anaerobic and partly aerobic glycolis; anorrhexogenic effects. Indications: Obese patients with type 2 DM, with middle severity of the disease without ketosis. They can be used with the combination of sulfanilureas when sulfonylureas alone have proved inadequate to treat DM. Contraindications: heart and lung disease with their insufficiency (chronic heart and lung failure); status with hypoxemia; acute and chronic liver and kidney diseases with decreased function; pregnant diabetics, lactation; old age;

 alcoholism; coma and precoma. Side effects: allergy; gastrointestinal tract disorders; lactoacidosis.

Alpha-glucosidase inhibitors (table 4) Acarbosa (Glucobay 50, 100 mg), miglitol. (It is taken with each meal, usually with first bolus f food). Table 4 . Commonly used alpha-glucosidase inhibitors Preparation Acarbose Action: Recommended dosage, Duration of action, times/day mg hours 150-300 6-8 6-8

inhibition of gastrointestinal tract absorption (blocation of -glucozidase); lowering of pastprandial glucose level (postprandial spikes in blood glucose are increasingly implicated as a major cause of cardiovascular complications); partly reducing fasting glucose levels by indirectly stimulating insulin secretion in patients who retain -cell function (and acarbose has a protective effect on cells). Contraindications: Chronic gastrointestinal disorders: pancreatitis, colitis, hepatitis. Side effects: flatulence, abdominal bloating, diarrhea.

Non-sulfanylureas insulin stimulators (table 5) Repaglinide (Novonorm 0,5 mg, 1 mg,2 mg). (Starting dose is 0,5 mg 15 20 min before each meal, maximum dose is 4 mg before each meal). Nateglinide (Starlix 0,06; 0,12; 0,18).

Table 5 . Commonly used non-sulfanylureas insulin stimulators Preparation Repaglinide Nateglinide Action: these drugs stimulates insulin production at meal times; very rapidly absorbed from the intestine and metabolized in liver; plasma half0life is less than 1 hour/ Indications: can be used in elderly with type 2 DM (due to short half-life) and in renal impairment (because it is metabolized in liver). Side effects: hypoglycemia; transient elevation of liver enzymes; rash; visual disturbances. Recommended dosage, Duration of action, times/day mg hours 0,5-16 3-4 3-4 120-480 3-4 3-4

Thiozolidindiones (table 6) Pioglitazon (Actos, Pionorm) Dose in 1 tabl. 0,015; 0,03; 0,045. Rosiglitazon is not used due to side effects Table 6 . Commonly used thiozolidindiones Preparation pioglitozon Recommended dosage, Duration of action, times/day mg hours 15-45 16-24 1

Action of thiozolidindiones Agonist to the receptors of the nucleus PPAR of the fat, muscle tissues and the liver; Increasing of the glucose passage to these tissues; Increasing of insulin synthesis in the b-cells; Increasing of the insulas amount;

 Increasing of glycogen synthesis in the liver; Decreasing of gluconeogenesis; Decreasing of triglycerides; Indications to thiozolidindiones usage DM type 2, when diet and exercises are no effective; Using with sulfanilureas, biguanides, insulin in case of their insufficient efficacy Contraindications to thiozolidindiones usage Diabetic coma, precoma, ketoacidosis; Acute and chronic diseases of the liver; Heart failure; Pregnancy, lactation; Children, teenagers; Allergic reactions to the drug. Side effects of thiozolidindiones Hypoglycemic conditions (rarely); Peripheral edema; Anemia; Obesity.

Incretin mimetics Exenatide (Byetta), liraglutide (Victoza) subcutaneous injection daily. Action: incretin effect is attributed to the insulinotropic action of gut hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Allows pancreas to release insulin. This drug lowers blood sugar levels only

when they rise too high. Prevents the pancreas from giving out glucagon. Helps to slow the rate at which stomach empties after eating. This may make

feel less hungry and more satisfied after a meal.

Indications: can be used in type 2 DM patients. Side effects: nausea (is usually worse during the first few weeks of treatment and gets better over time); diarrhea; stomch pain; pancreatitis; weight loss.

Incretin enhansers (table 7) Onglyza 5 mg Galvus 50 mg Yanuvia 25 mg, 50 mg, 100 mg Table 7 . Commonly used inhibitors of DPP IV Preparation saxagliptine (onglyza) vildagliptine (galvus) sitagliptine (yanuvia) Action: Suppress the degradation of a variety of bioactive peptides, including GLP-1, Recommended dosage, Duration of action, times/day mg hours 5 24 1 50-100 100-200 10-12 16-24 2 2

thereby extending their period of action by inhibing of dipeptydpeptidase IV (DPPIV). Indications: can be used in type 2 DM patients. Side effects: nasopharyngitis; mild headache;

 cough. Combined preparates Glibomet consists of Maninil 2,5 mg and Siofor 400 mg Plants therapy (phytotherapy). 1) hypoglycemic action; 2) treatment of chronic diabetics complications; 3) influence on the immune reactivity.

Insulin Insulin has been available for the treatment of patients with DM since 1921. For many years, the most commonly used preparations consisted of a combination of pancreatic bovine and porcine insulin. Contamination of small amounts (to 2 %) of other pancreatic hormones, such as glucagon, proinsulin, C peptide, somatostatin, and pancreatic polypeptide, was the rule. Subsequent purification have yielded purer (almost 100 %) preparations of beef insulin, pork insulin, or combination of two, with a biologic activity of 26 to 28 units/mg as compared to 22 to 24 units/mg for the older preparations. The most recent development has been the preparation of biosynthetic human insulin. Two procedures have been utilized. In the first, alanine in the 30 position of the B chain of pork insulin is substituted enzymatically by threonine. The resulting humanized pork insulin has the amino acid sequence of human insulin (Actrapid, Monotard made by Novo-Nordisk). The second approach involves synthesis by Escherichia coli (E. Coli) by recombinant DNA technology. The hormone can be produced by single fermentation in which proinsulin is made first and then cleaved into insulin and C peptide, or by separate fermentation in which A and B peptide are synthesized first and then joined into insulin (Humulin, Lilly). Synthetic human insulin does not have great advantages over purified pork insulin, except for slightly faster onset of the action. Hypokalemia, C-peptide suppression, and secretion of epinephrine, cortisol, growth hormone and prolactine may be reduced with human insulin. The synthetic hormone has the potential to be less antigenic than the pork insulin. Causes of

potential use for human insulin include resistance to exogenous insulin, beef or pork insulin allergy, lipodystrophy, gestation diabetes. Anticipated short-term administration, and newly diagnosed young diabetic patients. A multitude of insulin preparations and insulin analogues are available, and the major difference in their duration of action (Table 8, 9). Figures on onset, peak and duration of action are applicable to normal non-insulin-treated subjects. Only short-acting insulins should be given intravenously; all the types can be injected only subcutaneously.

Table 8. Insulin preparations Group Short-acting Preparations Humodar R Actrapid HM Iletin Humodar B Protaphan HM Humulin L Monotard MC Ultratard HM Ultralong Humodar C15 Mixtard 30 HM Monodar C-30 Onset, h 0,5 1,0 Peak of action, h 14 6 12 Duration of action, h 58 18 26

Intermediateacting

1-3

Long-acting Combined preparations

4-8 0,5

14 20

20 36

Depends on quantity of components

Table 9. Insulin analogues Group Ultra-short- acting (insulin analogues for rapid onset of insulin action) Long-acting inulin Preparations Humalog Hovorapid Epaidra Lantus Levemir Detmir Onset, h 5 - 10 min. Peak of action, h 0,5 2,5 Duration of action, h 3-4

nonpeaked

24

Indications for insulin therapy

1. All patients with type 1 DM. 2. Some patients with type 2 DM: uncontrolled diabetes by diet or oral hypoglycemic agents; ketoacidosis, coma; acute and chronic liver and kidneys disease with decreased function; pregnancy and lactation; II IV stages of angiopathy; infection diseases; acute heart and cerebral diseases; surgery.

Initiation and modification of insulin therapy to achieve diabetic control. The daily insulin requirement in patients: - on the first year of the disease is 0,3 0,5 unite of insulin per kilogram of body weight (0,5 if the patient with ketosis or DKA); - on the next years is 0,6 0,8 1,0 unite/ kg of body weight. We can use traditional or multiple component insulin program. The last is better. It using three or four shots of short-acting insulin (1/3 of total daily dose) plus intermediateacting (2/3 of total daily dose) insulin daily is started as soon as possible in an attempt to rest the damaged islet cells and help to induce a remission (honeymoon phase). Other advantages include the following: - hypoglycemic reactions may be decreased or prevented because smaller doses of insulin are needed; - more physiologic match of insulin to meals is achieved. 2/3 of the total daily dose we give before lunch, 1/3 in the evening and then make correction due to the glucose blood level. Insulin doses should be given 30 minutes before meals to allow for adequate absorption of regular insulin.

(Other commonly used insulin treatment algorithms: 1. Single prebreakfast injection of intermediate-acting insulin.

2. Intermediate-acting insulin: prebreakfast injection of 2/3 total daily dose, 1/3 of daily dose before dinner. 3. Combination of intermediate- and short-acting insulin: - single prebreakfast injection of 2/3 intermediate-acting + 1/3 of short-acting; - 2/3 before breakfast, 1/3 before lunch+dinner; 2/3 of it intermediate-acting, 1/3 short-acting. 4. Short-acting insulin hour before each meal and a small dose of intermediateacting insulin at bedtime. 5. Combination of long-acting (in prebreakfast time) and short-acting insulin (1/2 hour before each meal. The same schemes are shown in table 10. Table 10. Regimens of insulintherapy Before breakfast intermediateacting + shortacting short-acting short-acting ultra short-acting insulin analogue ultra short-acting insulin analogue + long-acting insulin analogue ) Some words about honeymoon stage. It results from a partial recovery of islet cell function (as measured by C-peptide). It occurs within 1 3 month after diagnosis and can last from weeks to a few month during which time insulin requirements fall drastically to less than 0,3 units/kg/day and in some, to no requirement for insulin at all. Insulin administration, however, is not discontinued during this time because of potential development of insulin allergy, as well as the need to reinforce the concept that type 1 DM is a lifelong illness without potential for true remission. Before lunch short-acting Before dinner short-acting At bedtime intermediateacting long-acting long-acting insulin analogue long-acting insulin analogue long-acting insulin analogue

short-acting short-acting ultra short-acting insulin analogue ultra short-acting insulin analogue

short-acting short-acting ultra short-acting insulin analogue ultra short-acting insulin analogue

Some particularities of insulin therapy: 1) insulin acts faster when is administrated intravenously; 2) subcutaneous and intramuscular absorption of insulin is decreased in the dehydrated or hypotensive patients; 3) it is necessary to change the insulin injection site (because the absorption is more rapid from the new sites); 4) the most rapid absorption from the abdomen; 5) exercise accelerates insulin absorption (before planned exercise program patient has to decrease insulin dose or take more caloric diet). Insulin is stable at room temperature, but refrigeration of the vial while not in use is recommended.

Future directions in improving glycemic control: nasal insulin preparations; pancreatic transplantation; islet replacement therapy; genetically engineered pseudo-beta-cells.

Side effects (complications) of insulin therapy. 1. Hypoglycemia. This complication represents insulin excess and it can occur at any time (frequently at night (common symptom: early-morning headache)). Precipitating factors: irregular ingesting of food; extreme activity; alcohol ingestion; drug interaction; liver or renal disease; hypopituitarism; adrenal insufficiency.

Treatment (preventing coma): to eat candy or to drink sweet orange juice (when the symptoms develop); to receive intravenous glucose; 1 mg of glucagon administrated subcutaneously; gradual reduction of insulin dose in future. Somogyi effect (Somogyi phenomenon, rebound effect) It is caused by overinsulinization: hyperglycemia proceeded by insulin induced hypoglycemia. Hypoglycemia causes an increase in the secretion of the counterregulatory hormones (glucagon, epinephrine, cortisol, growth hormone), which inhibit insulin secretion and increase glucose output by the liver (as a result of the stimulation of glucogenolysis and glucogenesis). Treatment: gradual reduction of insulin dose. Dawn phenomenon Many patients with type I DM demonstrate an early morning (4 8 a.m.) rise in glucose levels, because of activation of counterregulatory hormones. It may be confused with the Somogyi phenomenon. Sampling of glucose levels throughout the night might help differentiate the two conditions. Treatment: some have recommended an earlier injection in the morning (5 6 a.m.), and most suggest a late evening (before bedtime) injection of intermediateacting insulin. 2. Allergic reactions. These include burning and itching at the site of insulin injection; skin rash; vasculaties; purpura and anaphylactic reaction. Treatment: antihistamines; changing of standard insulin to pure pork insulin or to human insulin; in extreme cases glucocorticoids. 3. Insulin resistance. Clinical status characterized by insulin resistance: obesity; therapy with oral contraceptives;

 glucocorticoid therapy; acromegaly; Cushings syndrome; acanthosis nigricans; chronic liver or renal disease. Non-true insulin resistance may be caused by long-time injections of insulin into the one site. 4. Lipodystrophy It is atrophy or hypertrophy of the adipose tissue, which occur at the site of insulin injection. Treatment: changing the site of injection; the usage of human insulin.

Exercise program. Exercise is an excellent adjunct to diet therapy, but it is very ineffective when used as the sole weight-reducing modality. Exercises must be clearly planned and depend on patients abilities and the physical condition, exclusion of the competitions elements. Exercises may be valuable adjunct to the management of the DM by: - lowering blood glucose concentration; - decreasing insulin requirements; - potentiation the beneficial effects of diet and other therapy. To prevent hypoglycemia, patients should carefully monitor glucose level and taking of insulin. Mostly they need to reduce the insulin dosage by 20 25 % on the day that strenuous exercises is planned. Patients education. 1) the nature of DM and importance of metabolic control; 2) the principles and importance of good nutrition and reasonable exercise program;

3) the principles of adequate foot, dental and skin care; 4) treatment of DM during the periods of illness; 5) techniques of insulin administration and measurement of urine and blood glucose level (if taking insulin); 6) recognition of hypoglycemia, its causes and methods of prevention; 7) the importance of general and specific measures to minimize in the best possible way diabetic complications and maintain of good overall health. There are several specialized sanatoriums in Truscavets, Myrgorod, Odessa with specialized school for diabetics

Literature: Textbook of Endocrinilogy/ edited by prof. Petro M. Bodnar/ Vinnytsya Nova Davidsons Essentials of Medicine /edited by J. Alastair Innes, Edinburg, UK ,

1.

Knyha, 2008 496 p. 2. Elsevier, 2009 P.329 414. 3. The Merck Manual of Diagnosis and Therapy (eighteenth Edition)/ Robert Berkow and others. published by Merck Research Laboratories, 2006 P. 1926 2058. B. Additional. 1. Mohammad Inam Danish Short Textbook of Medical Diagnosis and Management (Third Edition). Pakistan, 2002 653 p.