10 management of patient with hypoglycemic coma. management of patient with hyperglycemic...

8/13/2019 10 Management of Patient With Hypoglycemic Coma. Management of Patient With Hyperglycemic (Ketoacidotic) …

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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)

↓ glucoseuptake

↑ proteolysis ↑ lipolysis

↑aminoa

cides

↑nitrogen

loss

Muscle break-

down

↑ glycerol

free fattyacids

weight

loss

↑ keto-

genesis

Weakn

ess

↑ keton-

emia

Hyperglycemia Gluconeogenesis+ glucogenolysis

↑ keton-uria

Glucosuria

Osmoticdiuresis

Electrolyte depletion

Hypotonic

losses

dehydration and acidosis

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.



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 patient’s 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 dextrose-

containing solutions

•

After stabilization of patient’s condition monitoring vital signs and recordingvalues 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 about11 – 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 2 % potassium solution

< 3 mmol/l 3 gr. 150 ml

3 – 4 mmol/l 2 gr. 100 ml

4 – 5 mmol/l 1,5 gr. 75 ml

5 – 6 mmol/l 1 gr. 50 ml

> 6mmol/l - -

Potassium would to be infused during 3 – 5 hours.



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 gram-

negative 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,



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 wasinvalidated 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 hyperglycemia-

induced osmotic diuresis.


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) occurover 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.


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 Lactic acid

NADH NAD

Acetoacetic 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.


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.


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.

DKA HNC LA

Age Below 40 Above 40 Above 40Type of DM Type 1 > type 2 Type 2 Type 2

Predisposing Insulin deficiency Dehydration Hypoxia



factor

Prodromes Several days

duration or less

than 1 day

Several days

duration

Less than 1 day

Underlying renal,

cardiovascular or

pulmonarydisease

About 15 % About 85 % About 90 %

General More acidic and

less dehydrated,hyperventilation

More dehydrated

and less acidic,no

hyperventilation

More acidic and less

dehydrated,hyperventilation

Neurologicsymptoms and

signs

Rare Very common Very common

Laboratoryfindings

- blood glucose

High (about 20 –

30 mmoll/l)

Very high (about

40 – 50 mmoll/l)

Normal or about 10 –

11 mmoll/l

- plasma ketones + - -

- serum sodium Normal, elevated

or low

Normal, elevated

or low

Normal

- serum potassium

Normal, elevatedor low

Normal, elevatedor low

Normal

- serum

bicarbonate

Low Normal Low

- blood pH Less than 7,35 Normal Less than 7,35

- serumosmolality

Less than 330mOsm/l

Over 350mOsm/l

Normal

- free fatty acids ↑ ↓or normal Normal

Complications:

- Thrombosis

- Mortality

Rare

1 – 10 %

Frequent

20 – 50 %

Very rare

About 90 %

Diabetes

treatment afterrecovery

Always insulin Diet alone or

oral agents,sometimes

insulin

Diet alone or oral

agents, sometimesinsulin

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.


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

Insulin – treated patients are advised to carry sugar lumps, candy, or glucosetablets 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 bestopped 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 19th-

century 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 atthe 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 The effects of insulin

carbohydratemetabolism

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)

http://www.britannica.com/EBchecked/topic/560613/spleen

http://www.britannica.com/EBchecked/topic/441006/pancreatic-duct

http://www.britannica.com/EBchecked/topic/173894/

http://www.britannica.com/EBchecked/topic/329670/islets-of-Langerhans

http://www.britannica.com/EBchecked/topic/63183/beta-cell

http://www.britannica.com/EBchecked/topic/36874/artery

http://www.britannica.com/EBchecked/topic/93807/capillary

http://www.britannica.com/EBchecked/topic/624704/vein

http://www.britannica.com/EBchecked/topic/409603/nerve-ending

http://www.britannica.com/EBchecked/topic/235785/glucagon

http://www.britannica.com/EBchecked/topic/553961/somatostatin

http://www.britannica.com/EBchecked/topic/441018/pancreatic-polypeptide

http://www.britannica.com/EBchecked/topic/441018/pancreatic-polypeptide

http://www.britannica.com/EBchecked/topic/553961/somatostatin

http://www.britannica.com/EBchecked/topic/235785/glucagon

http://www.britannica.com/EBchecked/topic/409603/nerve-ending

http://www.britannica.com/EBchecked/topic/624704/vein

http://www.britannica.com/EBchecked/topic/93807/capillary

http://www.britannica.com/EBchecked/topic/36874/artery

http://www.britannica.com/EBchecked/topic/63183/beta-cell

http://www.britannica.com/EBchecked/topic/329670/islets-of-Langerhans

http://www.britannica.com/EBchecked/topic/173894/

http://www.britannica.com/EBchecked/topic/441006/pancreatic-duct

http://www.britannica.com/EBchecked/topic/560613/spleen



The result of these actions is a reduction in blood glucose

concentration

Protein metabolism the transfer of amino acids across plasma membranes

stimulation of protein synthesis

inhibition of proteolysis

Lipid metabolism incorporation of fatty acids from circulating triglyceride

into adipose triglyceride stimulation of lipid synthesis

inhibition of lipolisis

Nucleic acids

metabolism stimulation of nucleic acid synthesis by stimulating the

formation of adenosine triphosphate (ATP), DNA and RNF

Other effects of insulin:

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 Action

glucagon stimulates glycogenolysis

stimulates glyconeogenesis

somatostatin inhibits secretion of insulin

regulates glucose absorption from alimentary tract into blood

glucocorticoids decrease of glucose utilization by tissues

stimulate glycogenolysis

stimulate glyconeogenesis

increase lipogenesis (in patients with insulin resistance)

catecholamines inhibits β-cells secretion

stimulates glycogenolysis

stimulates ACTH secretion

somatotropin stimulates α-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

ACTH stimulates glucocorticoides secretion and β-cells secretion

thyroid hormones increase glucose absorption into blood

stimulate glycogenolysis

inhibit fat formation from the carbohydrates

DIABETES MELLITUS



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 treatmentis 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 doesn’t 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 doesn’t “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 β-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 β-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; Cushing’s syndrome; pheochromocytoma;

glucagonoma, thyrotoxicosis, aldosteroma, somatostatinoma)

drug- or 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 pesticidein 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 DR 3, DR 4 or DR 3/DR 4; on the other hand, HLA DR 2 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. A genetic predisposition or changes of immunity.

II.

Putative environmental triggers.III. Active autoimmune insulities with β-cells destruction.

IV. Progression of autoimmune insulities with destruction of >50 % of β-cells.

V. Development of manifest DM (table 1).

VI. Total β-cells destruction.

Pathophysiology of DM

Insulin

lack

Defective polymorphonuclear function → infection

↑

Hyperglycemia → glucosurea → polyurea → dehydration

↓

Hyperosmolality

Proteolysis → weight loss → muscle wasting → polyphagia

Lipolysis → free fatty acid release → ketosis → acidosis

Table 1. The classic manifestation of diabetes mellitus

Signs and

symptomsMechanism of their development

Polyurea - 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;

Polydipsia - as more water is excreted, the body requires more water intake; Polyphagia - this occurs to lack of energy;

loss of weight - energy (calories) is lost as glucose in the urine. Loss of water

itself also contributes to weight loss. Increased proteolysis with



mobilization of aminoacids leads to enhancement of protein

catabolism and loss of weight, notably in muscle mass;

fatigue and

weakness

- probably occur as a result of decreased glucose utilization and

electrolyte abnormalities;

acidosis - develops due to increased lipolysis which cause the release of

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 potentialloss 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.


Skin

The skin is a common target of DM. Many lesions can be observed, but none isspecific 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 tissueThe 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 long-

standing 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 in250 ml of water.

Table 2. Interpretation of glucose tolerance test results

DiagnosisThe level of capillary blood glucose, mmol/l

Fast 2 hours after glucose intake

Normal 3,3 – 5,5 <7,8

Impaired fast glycemia 5,5 – 6,1 <7,8

Impaired glucose tolerance 5,5 – 6,1 7,8 – 11,1

Diabetes mellitus (table 3) >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 Type 1 DM Type 2 DM

1. Age Young (under 40) Old, moderate (over 40)

2. Beginning of disease Acute Gradual

3. Duration Labile Stable

4. Ketosis, ketoacidosis Often develops Rare develops

5. Body weight Decreased or normal Obesity in 80-90%of patients

6. Treatment Insulin, diet Diet, oral hypoglycemic



agents or insulin

7. Degrees of severity

(table 4)

Moderate, severe Mild, moderate, severe

8. Season of disease

beginning

Frequently autumn-winter

period

Absent

9. Connection with HBA-

system

Present Absent

10. Level of insulin and C- peptide

Decreased or absent Frequently normal level

11. Antibodies to β-cells Present in 80-90% of

patients on first year

Absent

12. Late complications Microangiopathies Macroangiopathies

13. Mortality Less than 10% More than 20%

14. Spreading 10-20% 80-90%

Table 4. Degrees of severity of DM

CriteriaDegree of severity

mild moderate Severe

compensation can

be achieved by

Diet oral hypoglycemic

agents (in patients

with type 2 DM) or

insulin (in patientswith type 1 DM)

by insulin or oral

hypoglycemic

agents

fast serum glucose

level, mmol/l

8,4 8,4 – 14,0 14,0

Glucosuria 20 gr. /l (2 %) 20 to 40 gr. /l (2 – 4

%)

40 gr. /l (4 %)

C o m p l i c a t i o n s

Acute

complications

proneness to

ketosis does not

occur

ketosis can occur ketosis is common,

frequent

hypoglycemia

long-term(chronic)

complications

are rare or onlyfunctional stages

can be observed

complications can beobserved (but not last

stages*)

last stages of long-term (chronic)

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:



1. Compensation.

2. Subcompensation.

3. Decompensation.

Criteria of compensative stage

1. Patient hasn’t 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 decompensation **

HBA1c, % <7,0 7,1 – 7,5 >7,5

Fast glucemia* 5,0 – 6,0 6,1 – 6,5 >6,5

Postprandial glucemia (in 2hours after meal intake)

7,5 – 8,0 8,1 – 9,0 >9,0

Glucemia at bedtime 6,0 – 7,0 7,1 – 7,5 >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).



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, stage or degree

Diabetes

mellitus

type

or as a result of

- 1

- 2- or to show a cause (in a case of another types of DM)

degree of severity - mild

- moderate

- severe

stage - compensation

- subcompensation

- decompensationdiabetic microangiopathy - nephropathy (stage)

- retinopathy (stage on each eye)

- angiopathy of lower extremities (stage)

diabetic neuropathy - peripheral

- autonomic (type)

- central

diabetic macroangiopathy - ischemic heart disease (type)

- heart failure (stage according NYHA)

- angiopathy of lower extremities (stage)syndrome of diabetic foot - ischemic

- neuropathic

- mixed

arterial hypertension degree

dyslipidemia in a case of presence

concomitant diseases

Example of diagnosis.

Diabetes mellitus type 1, severe degree, stage of subcompensation. Diabetic

peripheral neuropathy. Diabetic preproliferative retinopathy. Diabetic nephropathy IVstage. 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 retinopathyDibetics 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

retinal microaneurysms, hard and soft

exudates, small quantity of hemorrhages

an ischemic zones

Preproliferative

retinopathy

- vascular

- exudative

- hemorrhagic

- ischemic

the same changes as in nonproliferative

stage but large quantity of retinal

hemorrhages, intraretinal microvascular

abnormalities and macular edema

Proliferative retinopathy - neovascular

- gliose

a hallmark of this complication is

neovascularization, i.e., growth of newvessels in areas of hypoperfusion.

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 afterrecognition 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

nephropathyCharacteristic

I. Hyperfunction

of kidneys

- increased renal blood circulation;

- increased glomerular filtration rate (GFR*) (> 140 ml/min);

- hypertrophy of kidneys;

- normoalbuminuria (<30 mg/day)

II. Stage of initial

changes of kidney

structure

- mesangial changes due to accumulation of immunoglobulins

(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

V. Chronic renal

failure or uremia

- decreased GFR;

- 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 bodysize, 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.



http://en.wikipedia.org/wiki/Chronic_kidney_disease#Stages_of_Chronic_Kidney_Disease

http://en.wikipedia.org/wiki/Proteinuria

http://en.wikipedia.org/wiki/Proteinuria

http://en.wikipedia.org/wiki/Chronic_kidney_disease#Stages_of_Chronic_Kidney_Disease




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 patient’s weight).

Stage IV

1-3 - as in stage I-III.

4. Restriction of animal protein in diet (≤ 0,8gr/1 kg of patient’s weight).

5. Correction of secondary anemia.

Stage V

1-5 – as in stage IV.6. Correction of electrolyte’s 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 Characteistic

I. Nonclinic stage Changes could be find only during instrumental examination

II. Functional stage 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).



- 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, andsyncope 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: ɑ- lipoid acid (dialipon, berlition, tiogama-

turbo), 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 of vascular

insufficiency, neuropathy, and infection.

Diabetic foot is divided on three types:



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 (plant’s 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 suchcase 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

Mechanism of action Oral hypoglycemic

agents

Insulin sensitizersIncrease sensitivity of tissues

to insulin

biguanides

thiazolidinediones

Insulin secretagogues Stimulation of insulin secretion

sulfanilureas

non-sulfanylureas insulin

stimulators

Incretin modulators

Incretin mimetics - mimic the

natural hormones in your body

that lower blood sugar

exenatide

liraglutide

Incretin enhansers – stimulateincretin hormones effects

vildagliptine

sitagliptine

saxagliptine

Alpha-glucozidase

inhibitors

Inhibite gastrointestinal tract

absorption

acarbose

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,mg Duration of action,hours times/day

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 β-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 Recommended dosage,

mg

Duration of action,

hours

times/day

metformine 500-3000 8-12 3

Action:

inhibition of gastrointestinal glucose absorption;

decreasing of glyconeogenesis, lipogenesis; enhancing glucose transport into muscle cells;

increasing the quantity of insulin’s 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


mg

Duration of action,

hours

times/day

Acarbose 150-300 6-8 6-8

Action:

inhibition of gastrointestinal tract absorption (blocation of α-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 β-cell function (and acarbose has a protective effect on β-

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


mg

Duration of action,

hours

times/day

Repaglinide 0,5-16 3-4 3-4

Nateglinide 120-480 3-4 3-4

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.

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


mg

Duration of action,

hours

times/day

pioglitozon 15-45 16-24 1

Action of thiozolidindiones

Agonist to the receptors of the nucleus PPAR γ 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.

http://www.webmd.com/hw-popup/insulin

http://www.webmd.com/digestive-disorders/picture-of-the-pancreas

http://www.webmd.com/hw-popup/glucagon

http://www.webmd.com/digestive-disorders/picture-of-the-stomach

http://www.webmd.com/digestive-disorders/picture-of-the-stomach

http://www.webmd.com/hw-popup/glucagon

http://www.webmd.com/digestive-disorders/picture-of-the-pancreas

http://www.webmd.com/hw-popup/insulin



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


mg

Duration of action,

hours

times/day

saxagliptine

(onglyza)

5 24 1

vildagliptine

(galvus)

50-100 10-12 2

sitagliptine(yanuvia)

100-200 16-24 2

Action:

Suppress the degradation of a variety of bioactive peptides, including GLP-1,

thereby extending their period of action by inhibing of dipeptydpeptidase IV (DPP-

IV).

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

Plant’s 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. Formany 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 Preparations Onset, h Peak ofaction, h Duration ofaction, h

Short-acting Humodar R

Actrapid HM

Iletin

0,5 – 1,0 1 – 4 5 – 8

Intermediate-

acting

Humodar B

Protaphan HM

Humulin L

Monotard MC

1 - 3 6 – 12 18 – 26

Long-acting Ultratard HMUltralong 4 - 8 14 – 20 20 – 36

Combined

preparations

Humodar C-

15

Mixtard 30

HMMonodar C-30

0,5 Depends on quantity of

components

Table 9. Insulin analogues

Group Preparations Onset, h Peak of

action, h

Duration of

action, h

Ultra-short- acting

(insulin analogues

for rapid onset of

insulin action)

Humalog

Hovorapid

Epaidra

5 - 10

min.

0,5 – 2,5 3 - 4

Long-acting inulin Lantus

Levemir

Detmir

1 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 intermediate-

acting (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 ½ hour before each meal and a small dose of intermediate-

acting 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 Before lunch Before dinner At bedtime

intermediate-

acting + short-

acting

short-acting short-acting intermediate-

acting

short-acting short-acting short-acting long-acting

short-acting short-acting short-acting long-acting

insulin analogueultra short-acting

insulin analogue

ultra short-acting

insulin analogue

ultra short-acting

insulin analogue

long-acting

insulin analogue

ultra short-acting

insulin analogue

+

long-acting

insulin analogue

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.



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 useis 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 intermediate-

acting 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;

Cushing’s 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 patient’s abilities and the

physical condition, exclusion of the competition’s 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.

Patient’s 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:

1. Textbook of Endocrinilogy/ edited by prof. Petro M. Bodnar/ Vinnytsya “Nova

Knyha”, 2008 – 496 p.

2. Davidson’s Essentials of Medicine /edited by J. Alastair Innes, Edinburg, UK ,

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.

10 management of patient with hypoglycemic coma. management of patient with hyperglycemic...

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