Diagnosis and treatment of diabetes mellitus and thyroid disorders in an outpatient setting. The principles of evidence-based medicine (epidemiology, standards of diagnosis, treatment algorithms ) in a family practice physician. Clinical supervision. Indications for hospitalization.

Diabetes Mellitus (DM) – is 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.

Insulin is a rather small protein, with a molecular weight of about 6000 Daltons. It is composed of two chains held together by disulfide bonds.

Structure of Insulin

Biosynthesis of Insulin

Insulin is synthesized in significant quantities only in B cells in the pancreas.

The insulin mRNA is translated as a single chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin.

Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide.

Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm.

When the B cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity.

Control of Insulin Secretion

Video

Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.

Our understanding of the mechanisms behind insulin secretion remain somewhat fragmentary. Nonetheless, certain features of this process have been clearly and repeatedly demonstrated, yielding the following model:

· Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell.

· Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the B cell cause depolarization is not clearly established, but seems to result from metabolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance.

· Increased levels of glucose within B cells also appears to activate calcium-independent pathways that participate in insulin secretion.

Stimulation of insulin release is readily observed in whole animals or people. The normal fasting blood glucose concentration in humans and most mammals is 80 to 90 mg per 100 ml, associated with very low levels of insulin secretion.

Immediately after the increasing the level of glycemia begins, plasma insulin levels increase dramatically. This initial increase is due to secretion of preformed insulin, which is soon significantly depleted. The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately. Clearly, elevated glucose not only simulates insulin secretion, but also transcription of the insulin gene and translation of its mRNA.

Physiologic effects of insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"

Insulin is a key player in the control of intermediary metabolism. It has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues.

The Insulin Receptor and Mechanism of Action

Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.

The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.

Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects.

The action of insuin

Insulin is an anabolic hormone (promotes the synthesis of carbohydrates, proteins, lipids and nucleic acids).

The most important target organs for insulin action are:

- liver

- muscles

- adipocytes.

The brain and blood cells are unresponsive to insulin.

Insulin and Carbohydrate Metabolism

Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue.

The effects of insulin on carbohydrate metabolism include:

1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues.

The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.

In the absense of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.

It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.

2. Insulin stimulates the liver to store glucose in the form of glycogen .

A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.

Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.

3. Insulin inhibits glucose formation – from glycogen (glycogenolysis) and – from amino-acid precursors (glyconeogenesis).

As aresult - well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.

In the absense of insulin, glycogen synthesis in the liver ceases and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.

Insulin and Protein Metabolism:

1. Insulin transfers of amino acids across plasma membranes.

2. Insulin stimulates of protein synthesis.

3. Insulin inhibites of proteolysis.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism. Important effects of insulin on lipid metabolism include the following:

1. Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.

When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

2. Insulin inhibits breakdown of fat in adipose tissue (lipolisis) by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat is adipose tissue.

Insulin and Nucleic acids Metabolism:

1. Insulin stimulates nucleic acid synthesis by stimulating the formation of adenosine triphosphate (ATP), DNA and RNF.

Other effects:

1. Insulin stimulates the intracellular flew of potassium, phosphate and magnesium in the heart.

2. Insulin inhibits inotropic and chronoropic action (unrelated to hypoglycemia).

The action of insulin can be decreased by:

- glucagons: stimulates glycogenolysis and glyconeogenesis;

- somatostatin: inhibits secretion of insulin and regulates glucose absorption from alimentary tract into blood;

- glucocorticoids: decrease of glucose utilization by tissues, stimulate glycogenolysis and glyconeogenesis, increase lipogenesis (in patients with insulinoresistancy);

- katecholamines (adrenaline): inhibits β-cells secretion, stimulates glycogenolysis and 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.

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 inflammative, 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, contrainsulin hormones, absence of enzyme, which activates proinsulin (into insulin));

- receptors (decreased receptor number or diminished binding of insulin).

Type 1, or insulin-dependent diabetes mellitus is characterized by pancreatic islet beta cell destruction and absolute insulinopenia.

Video – Diabetes type 1

Video – Pathogenesis of DM type 1

This individuals 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.

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, mumps) 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.

Normal β-cells

II. Putative environmental triggers.

III. Active autoimmune insulities with β-cells destruction.

Insulinitis

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

V. Development of manifest DM.

VI. Total β-cells destruction.

β-cells destruction

Type 2 or non-insulin-dependent diabetes mellitus is the most common form of diabetes, accounting for 95 – 90 % of the diabetic population. (Video) Most investigators agree that genetic factors underlie NIDDM, 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. In patients with type 2 DM mostly we can find relative insulin insufficiency (when pancreatic gland secrets insulin but it can have changed structure or weight, or circulating enzymes and antibodies destroy normal insulin, or there are changes of insulin receptors).

Video 1

Video 2

Video 3

Video 4

Pathogenetic and clinical difference of type 1 and type 2 DM.

	Signs	Type 1 DM	Type 2 DM
1.	Age	Young (under 40)	Old, middle (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	Middle, hard	Mild, middle, hard
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 week, month	Absent
12.	Late complications	Microangiopathies	Macroangiopathies
13.	Mortality	Less than 10%	More than 20%
14.	Spreading	10-20%	80-90%

Etiologic classification of DM (WHO, 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;

- genetic defects of insulin action;

- pancreatic diseases (chronic pancreatitis; trauma, pancreatectomy; tumor of pancreatic gland; fibrocalculosis; hemochromatosis);

- endocrine disease;

- drug exposures;

- infections and others.

IV. Gestation diabetes.

(Gestation diabetes is defined as hyperglycemia diagnosed for the first time in pregnancy. It occurs in individuals who have an inherited predisposition to develop diabetes and may take the form of either type 1 or type 2 diabetes. Gestation diabetes is associated not only with increased rate of perinatal morbidity and neonatal mortality but also with high incidence of subsequent diabetes in mother. Treatment is with diet modification and insulin. Insulin does not cross placenta while oral hypoglycemic agents cross placenta and therefore contrindicated.)

Stages of DM development

1. Prediabetes (risk factors or predispose factors):

- Obesity (pict.);

- 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;

= furunculosis;

= rubella, mumps, coxsackie virus, infectious hepatitis, cytomegalovirus, infection mononucleosis.

2. Impaired glucose tolerance (latent DM).

3. Clinical manifestation of DM.

Degrees of severity of DM

1. Mild degree:

1) compensation can be achieved by diet;

2) fast serum glucose is less than 8.4 mmol/l;

3) glucosuria less than 20 gr./l (2 %);

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

2. Moderate degree:

1) compensation can be achieved by oral hypoglycemic agents (in patients with type 2 DM) or insulin (in patients with type 1 DM);

2) fast serum glucose is 8.4 to 14.0 mmol/l;

3) glucosuria is 20 to 40 gr./l (2 – 4 %);

4) ketosis can occur; long-term (chronic) complications can be observed (but not last stages).

3. Severe degree:

1) compensation can be achieved by insulin or oral hypoglycemic agents;

2) fast serum glucose is over 14,0 mmol/l;

3) glucosuria is over 40 gr./l (4 %);

4) ketosis is common and last stages of long-term (chronic) complications are present.

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 8.0 mmol/l in patients which haven’t complications and under 11.0 mmol/l in patients with long-term complications).

3. Glucose in urine is absent.

4. Glucose level fluctuation is under 4.4-5.5 mmol/l during the day .

5. Comatose and precomatose status are absent.

6. HbA1c <7,0 % (DM type 1), <6,5% (DM type 2)

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. Comatose or precomatose status are absent.

6. HbA1c 7,0 – 7,5 % (DM type 1), 6,5 – 7,0 % (DM type 2)

Criteria of decompensative stage:

1. Comatose or precomatose status are present.

2. HbA1c >7,5 % (DM type 1), >7<0% (DM type 2).

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).

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

Clinical presentation

Signs and symptoms.

Video

The classic manifestation of type1 DM include :

Video 1

Video 2

- 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);
- polidipsia	(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).

Presenting signs and symptoms of type2 DM include: polyurea, polydipsia, polyphagia; the majority of individuals (80 – 85 %) are obese, but it can also occur in lean persons.

Video

Patients with DM are at risk if developing of chronic degenerative complications.

Physical examination.

Skin

Diabetes can affect every part of the body, including the skin. The skin is a common target of DM As many as one third of people with diabetes will have a skin disorder caused or affected by diabetes at some time in their lives. In fact, such problems are sometimes the first sign that a person has diabetes. Luckily, most skin conditions can be prevented or easily treated if caught early.

Some of these problems are skin conditions anyone can have, but people with diabetes get more easily. These include bacterial infections, fungal infections, and itching. Other skin problems happen mostly or only to people with diabetes. These include diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive xanthomatosis.

Bacterial Infections

Several kinds of bacterial infections occur in people with diabetes. One common one are styes. These are infections of the glands of the eyelid. Another kind of infection are boils, or infections of the hair follicles. Carbuncles are deep infections of the skin and the tissue underneath. Infections can also occur around the nails.

Inflamed tissues are usually hot, swollen, red, and painful. Several different organisms can cause infections. The most common ones are the Staphylococcus bacteria, also called staph.

Once, bacterial infections were life threatening, especially for people with diabetes. Today, death is rare, thanks to antibiotics and better methods of blood sugar control.

But even today, people with diabetes have more bacterial infections than other people do.

Fungal Infections

The culprit in fungal infections of people with diabetes is often Candida albicans. This yeast-like fungus can create itchy rashes of moist, red areas surrounded by tiny blisters and scales. These infections often occur in warm, moist folds of the skin. Problem areas are under the breasts, around the nails, between fingers and toes, in the corners of the mouth, under the foreskin (in uncircumcised men), and in the armpits and groin.

Common fungal infections include jock itch, athlete's foot, ringworm (a ring-shaped itchy patch), and vaginal infection that causes itching.

Itching

Localized itching is often caused by diabetes. It can be caused by a yeast infection, dry skin, or poor circulation. When poor circulation is the cause of itching, the itchiest areas may be the lower parts of the legs.

Diabetic Dermopathy

Diabetes can cause changes in the small blood vessels. These changes can cause skin problems called diabetic dermopathy.

Dermopathy often looks like light brown, scaly patches. These patches may be oval or circular. Some people mistake them for age spots. This disorder most often occurs on the front of both legs. But the legs may not be affected to the same degree. The patches do not hurt, open up, or itch.

Necrobiosis Lipoidica Diabeticorum

Another disease that may be caused by changes in the blood vessels is necrobiosis lipoidica diabeticorum (NLD). NLD is similar to diabetic dermopathy. The difference is that the spots are fewer, but larger and deeper.Iit consists of skin necrosis with lipid infiltration and is also characteristically found in the pretibial area. The lesions resemble red plaques with distinct border.s

NLD often starts as a dull red raised area. After a while, it looks like a shiny scar with a violet border. The blood vessels under the skin may become easier to see. Sometimes NLD is itchy and painful. Sometimes the spots crack open.

NLD is a rare condition. Adult women are the most likely to get it. As long as the sores do not break open, you do not need to have it treated. But if you get open sores, see your doctor for treatment.

Atherosclerosis

video

Thickening of the arteries - atherosclerosis - can affect the skin on the legs. People with diabetes tend to get atherosclerosis at younger ages than other people do.

As atherosclerosis narrows the blood vessels, the skin changes. It becomes hairless, thin, cool, and shiny. The toes become cold. Toenails thicken and discolor. And exercise causes pain in the calf muscles because the muscles are not getting enough oxygen.

Because blood carries the infection-fighting white cells, affected legs heal slowly when the skin in injured. Even minor scrapes can result in open sores that heal slowly.

People with neuropathy are more likely to suffer foot injuries. These occur because the person does not feel pain, heat, cold, or pressure as well. The person can have an injured foot and not know about it. The wound goes uncared for, and so infections develop easily. Atherosclerosis can make things worse. The reduced blood flow can cause the infection to become severe.

Allergic Reactions

Allergic skin reactions can occur in response to medicines, such as insulin or diabetes pills. You should see your doctor if you think you are having a reaction to a medicine. Be on the lookout for rashes, depressions, or bumps at the sites where you inject insulin.

Diabetic Blisters (Bullosis Diabeticorum)

Rarely, people with diabetes erupt in blisters. Diabetic blisters can occur on the backs of fingers, hands, toes, feet, and sometimes, on legs or forearms.

These sores look like burn blisters. They sometimes are large. But they are painless and have no redness around them. They heal by themselves, usually without scars, in about three weeks. They often occur in people who have diabetic neuropathy. The only treatment is to bring blood sugar levels under control.

Eruptive Xanthomatosis

Pict. Eruptive xanthomas are usually associated with very high serum triglycerides or chylimicrones. They may occur in familial chylomicronaemia syndrome, lipoprotein lipase deficiency, severe familial hypertriglyceridemia, excess alcohol intake, severe uncontrolled diabetes. Treatment is to correct the underlying condition. Lowering triglycerides will result in the clearance of the lesions.

Pict. Tendon xanthomas are shown in the extensor tendons of the hand. These cutaneous lesions are cholesterol ester deposits and are an important cutaneous manifestation of familial hypercholesterolemia, diabetes mellitus.

Pict. This shown classic xanthelasma around the eye. It may be associated with genetic hyperlipidaemias, although it may occur with diabetes, biliary cirrhosis or without any associated conditions.

Eruptive xanthomatosis is another condition caused by diabetes that's out of control. It consists of firm, yellow, pea-like enlargements in the skin. Each bump has a red halo and may itch. This condition occurs most often on the backs of hands, feet, arms, legs, elbows, knees and buttocks.

The disorder usually occurs in young men with type 1 diabetes. The person often has high levels of cholesterol and fat (particularly hyperchylomicronemia) in the blood. Like diabetic blisters, these bumps disappear when diabetes control is restored.

Digital Sclerosis

Sometimes, people with diabetes develop tight, thick, waxy skin on the backs of their hands. Sometimes skin on the toes and forehead also becomes thick. The finger joints become stiff and can no longer move the way they should. Rarely, knees, ankles, or elbows also get stiff.

This condition happens to about one third of people who have type 1 diabetes. The only treatment is to bring blood sugar levels under control.

Disseminated Granuloma Annulare

In disseminated granuloma annulare, the person has sharply defined ring-shaped or arc-shaped raised areas on the skin. These rashes occur most often on parts of the body far from the trunk (for example, the fingers or ears). But sometimes the raised areas occur on the trunk. They can be red, red-brown, or skin-colored.

Acanthosis Nigricans

Acanthosis nigricans is a condition in which tan or brown raised areas appear on the sides of the neck, armpits, and groin. Sometimes they also occur on the hands, elbows, and knees.

Acanthosis nigricans usually strikes people who are very overweight. The best treatment is to lose weight. Some creams can help the spots look better.

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 and joints

• Osteoporosis, osteoarthropaphy, diabetic chairopathy (decreasing of the movements of joints) can be find in patients with DM also.

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.

Video

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. 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 intermittent claudication, cold extremities, numbness, tingling and gangrene.

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 glomerulonephritides, infections can occur in any part of the urinary tract. Last are caused when bacteria, usually from the digestive system, reach the urinary tract. If bacteria are growing in the urethra, the infection is called urethritis. The bacteria may travel up the urinary tract and cause a bladder infection, called cystitis. An untreated infection may go farther into the body and cause pyelonephritis, a kidney infection. Some people have chronic or recurrent urinary tract infections.

Pict.There is thicken of basement membranes and mesangial expansion and Kimmelstiel - Wilson nodule

Symptoms of urinary tract infections may include

• a frequent urge to urinate
• pain or burning in the bladder or urethra during urination
• cloudy or reddish urine
• fatigue or shakiness
• in women, pressure above the pubic bone
• in men, a feeling of fullness in the rectum

Obviously, these abnormalities, with exception of diabetic nephropathy, are not at all peculiar to DM and can be observed in many other conditions.

Eyes

Complications of the eyes include: ceratities, retinatis, chorioretinatis, 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).

Pict. Cataracta

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:

I. Clinical manifestations of DM.

II. Laboratory findings.

1) fasting serum glucose (if the value is over 6,7 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.

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 antercubital vein before glucose ingestion and every 30 minutes far 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;

- the criteria for diagnosing diabetes in pregnant, adults are:

	Fasting serum glucose, mmol/l	2 hours after glucose loading, mmol/l
	Capillary blood
Health	3,3 – 5,5	<7,8
Impaired glucose tolerance	5,6 – 6,1	7,8 – 11,1
Diabetes mellitus	> 6,1	> 11,1
Impaired fast glucose tolerance	5,6 – 6,1	< 7,8

a) a fasting serum glucose more than 6,1 mmol/l (120 gm/dl);

b) a 2-hour postprandial serum glucose over 11,1 mmol/l (200 gm/dl);

- the criteria for diagnosing of impaired glucose tolerance are:

a) a fasting serum glucose more than 5,5 mmol/l (100 gm/dl);

b) a 2-hour postprandial serum glucose more than 7,8 mmol/l (140 gm/dl) but less than 11,1 mmol/l (200 gm/dl).

The major indication for an oral GTT is to exclude or diagnose DM (mostly 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) islet cell antibody levels will be positive prior to any insulin administration in 60 – 80 % of patients with type 1 DM;

4) 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);

5) glucose level in urine;

6) glycohemoglobin (Hb1Ac) (this test is an indicator of blood sugar control during the previous 2-to-3-month period);

7) acetonurea;

8) blood lipids and others.

III. Instrumental investigations usually are used to diagnose chronic complications of DM.

Long-term (late) complications

of diabetes mellitus (DM):

classification and diagnostic criteria.

Classification of chronic (long-term) complications of DM.

I. Diabetic angiopathy:

1. Microangiopathy:

1) nephropathy;

2) retinopathy;

3) angiopathy of lower extremitas.

2. Macroangiopathy:

1) ischemic heart disease;

2) angiopathy of lower extremities.

II. Diabetic neuropathy:

1) central (encephalopathy);

2) peripheral;

3) visceral (dysfunction of inner organs).

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.

Diabetic retinopathy.

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 1DM, is present in up to 20 % of type 2 DM patients at diagnosis. About 85 % of all diabetics eventually develop some degree of retinopathy.

Video

Video 2

Video 3

Diabetic retinopathy is classified according to the changes seen at background during ophthalmoscopic examination with pupils dilated.

I. Nonproliferative or background retinopathy (it is usually the earliest sigh and consists of retinal microaneurysms, hard and soft exudates).

II. Maculopathy or preproliferative retinopathy (it is characterized by macular edema and/or hemorrhages).

III. Proliferative retinopathy (the hallmark of this complication is neovascularization, i.e., growth of new vessels in areas of hypoperfusion. Adhesion of the vessels to the vitreous leads to retinal detachment, vitreous hemorrhage 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 metabolitic abnormalities particularly of lipids, have been implicated.

Diabetic nephropathy.

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 histologic lesion of DM.

Video

Pict. In the first few years of type 1 DM there is hyperfiltration which declines fairly steadily to return to a normal value at approximately 10 years (blue line). After sbout 10 years there is sustained proteinurea and by approximately 14 years it has reached nephritic stage (red line). Renal function continues to decline, with the end stage being reached at approximately 16 years

Classification of diabetic nephropathy by Mogensen.

I. Hyperfunction of kidneys. (It is characterized by:

- 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. (It is characterized by:

- mesangial changes due to accumulation of immunoglobulins (IgG, IgM), complement and other nonimmunologic proteins (lipoproteins, fibrin);

- high GFR;

- normoalbuminuria.)

III. Initial nephropathy. (It is characterized by:

- microalbuminuria (30 to 300 mg/day);

- high or normal GFR;

- periods of blood hypertension.)

IV. Nephropathy or nephrotic stage. (It is characterized by:

- persistent proteinurea (>500 mg/day);

- normal or decreased GFR;

- persistent blood hypertension.)

V. Chronic renal failure or uremia.. It is characterized by:

Physical signs of chronic renal failure

- decreased GFR;

- blood hypertension;

- increased serum creatinine;

- signs of intoxication.

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).

Classification of lower extremities’ angiopathy.

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.)

Ischemic heart disease.

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 nondiabetis og 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 demyelination.

Classification of diabetic neuropathy.

I. Encephalopathy (central neyropathy) is characterized by decreased memory, headache, unadequate actions and others.

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 responce 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 thorasic nerves and the findings are limited to the sensory abnormalities in a radicular distribution.).

III. Visceral dysfunction:

When you want to lift your arm or take a step, your brain sends nerve signals to the appropriate muscles. Internal organs like the heart and bladder are also controlled by nerve signals, but you do not have the same kind of conscious control over them as you do over your arms and legs. The nerves that control your internal organs are called autonomic nerves, and they signal your body to digest food and circulate blood without your having to think about it. Your body's response to sexual stimuli is also involuntary, governed by autonomic nerve signals that increase blood flow to the genitals and cause smooth muscle tissue to relax. Damage to these autonomic nerves is what can hinder normal function.

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) cardiovascular system:

- 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.);

- tachicardia (but it does not occur in response to hypotension because of sympathetic involvement).

3) urinary tract:

- Bladder dysfunction can have a profound effect on quality of life. Diabetes can damage the nerves that control bladder function. Men and women with diabetes commonly have bladder symptoms that may include a feeling of urinary urgency, frequency, getting up at night to urinate often, or leakage of urine (incontinence). These symptoms have been called overactive bladder. Less common but more severe bladder symptoms include difficulty urinating and complete failure to empty (retention). These symptoms are called a neurogenic bladder. Some evidence indicates that this problem occurs in both men and women with diabetes at earlier ages than in those without diabetes.

Neurogenic Bladder

In neurogenic bladder, damage to the nerves that go to your bladder can cause it to release urine when you do not intend to urinate, resulting in leakage. Or damage to nerves may prevent your bladder from releasing urine properly and it may be forced back into the kidneys, causing kidney damage or urinary tract infections.

Neurogenic bladder can be caused by diabetes or other diseases, accidents that damage the nerves, or infections.

Symptoms of neurogenic bladder include

• urinary tract infections
• loss of the urge to urinate when the bladder is full
• leakage of urine
• inability to empty the bladder

4) sexual disorders:

Sexual Problems in Men With Diabetes

Erectile Dysfunction

Estimates of the prevalence of erectile dysfunction in men with diabetes range from 20 to 85 percent. Erectile dysfunction is a consistent inability to have an erection firm enough for sexual intercourse. The condition includes the total inability to have an erection, the inability to sustain an erection, or the occasional inability to have or sustain an erection. A recent study of a clinic population revealed that 5 percent of the men with erectile dysfunction also had undiagnosed diabetes.

Men who have diabetes are three times more likely to have erectile dysfunction as men who do not have diabetes. Among men with erectile dysfunction, those with diabetes are likely to have experienced the problem as much as 10 to 15 years earlier than men without diabetes.

In addition to diabetes, other major causes of erectile dysfunction include high blood pressure, kidney disease, alcoholism, and blood vessel disease. Erectile dysfunction may also occur because of the side effects of medications, psychological factors, smoking, and hormonal deficiencies.

If you experience erectile dysfunction, talking to your doctor about it is the first step in getting help. Your doctor may ask you about your medical history, the type and frequency of your sexual problems, your medications, your smoking and drinking habits, and other health conditions. A physical exam and laboratory tests may help pinpoint causes. Your blood glucose control and hormone levels will be checked. The doctor may also ask you whether you are depressed or have recently experienced upsetting changes in your life. In addition, you may be asked to do a test at home that checks for erections that occur while you sleep.

Retrograde Ejaculation

Retrograde ejaculation is a condition in which part or all of a man's semen goes into the bladder instead of out the penis during ejaculation. Retrograde ejaculation occurs when internal muscles, called sphincters, do not function normally. A sphincter automatically opens or closes a passage in the body. The semen mixes with urine in the bladder and leaves the body during urination, without harming the bladder. A man experiencing retrograde ejaculation may notice that little semen is discharged during ejaculation or may become aware of the condition if fertility problems arise. His urine may appear cloudy; analysis of a urine sample after ejaculation will reveal the presence of semen.

Poor blood glucose control and the resulting nerve damage are associated with retrograde ejaculation. Other causes include prostate surgery or some blood pressure medicines.

Sexual Problems in Women With Diabetes

Decreased Vaginal Lubrication

Nerve damage to cells that line the vagina can result in dryness, which in turn may lead to discomfort during sexual intercourse. Discomfort is likely to decrease sexual response or desire.

Decreased or Absent Sexual Response

Diabetes or other diseases, blood pressure medications, certain prescription and over-the-counter drugs, alcohol abuse, smoking, and psychological factors such as anxiety or depression can all cause sexual problems in women. Gynecologic infections or conditions relating to pregnancy or menopause can also contribute to decreased or absent sexual response.

As many as 35 percent of women with diabetes may experience decreased or absent sexual response. Decreased desire for sex, inability to become or remain aroused, lack of sensation, or inability to reach orgasm can result.

Symptoms include

· decreased or total lack of interest in sexual relations

· decreased or no sensation in the genital area

· constant or occasional inability to reach orgasm

· dryness in the vaginal area, leading to pain or discomfort during sexual relations

Neuropathic arthropathy (Charcot’s joints)

is characterized by painless swelling of the feet without edema or signs of infection. The foot becomes shorter and wider, eversion, external rotation, and flattening of the longitudinal arch. This arthropathy is associated with sensory involvelvement, particularly impairment of afferent pain proprioceptive impulses.

Diabetic foot.

Appearance of diabetic foot is caused by a combination of vascular insufficiency, neuropathy, and infection.

Diabetic foot is divided on:

- ischemic;

- neuropathy;

- mixed.

	Ischemic	Neuropatic
Temperature of the skin	decreased	normal
Color of the skin	pallor or cyanotic	normal or pink
Pulsation on peripheral vessels	decreased or absent	normal
Odema	absent	can be
Sensibility	partly decreased or normal	decreased or absent
Ulcers	peripheral (distant)	under the pressure
Gangrene	Dry	moist

Pict. Pressure is increased in front of the first metatarsophalangeal joint.

Neuropathy may contribute to this disorder. Hyperkeratosis and secondary ulceration may occur.

Video

The main principles of Diabetes Mellitus 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:

1. Diet.

2. Oral hypoglycemic agents or insulin (indications for each vary with the type of DM and severity of the disease).

Treatment of diabetes mellitus

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.

Picture (b) is more appropriate according to guidelines for diabetic diet (i.e.products with low glycaemic profile).

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 I DM (35-50 kcal/kg of ideal weight (weight = height – 100)) and low-calorie diet in obese persons (mostly in patients with type II 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 II DM. The most commonly used are: the sulfanilureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones (potentiation of insulin action, glitazones), glinides (non-sulfanylureas insulin stimulators).

Principal modes and sites of action of pharmacologic treatment for type 2 diabetes

Sulfanilureas include:

- first generation: Tolbutamide, Chlorpropamide, Tolazemide, Acetohexamide (now are not used in treatment of the diabetics);

- second generation: Glibenclamide (Maninil), Glipizide (Glurenorm), Gliquidon;

2 nd generation drugs (mg)	Mg in 1 tabl	Daily dose	Duration of action	Peculiarities
Glibenclamid (Maninil, Euglucan, Daonil, Glinil, Gilamat, Gliben, Glucoven)	1; 1,75; 3,5; 5	1-2	12-24
Glibornurid (Glutrid)	25	25-75	8-12
Gliquidon (Glurenorm, Beglicor)	30	30-120	8-12	Without hepato- and nephrotoxic effects, metabolism through the intestinum
Gliclazid (Diamicron, Diabeton, Predian, Glizid) Diabeton MR	80 30	80-320 30-120	8-12 24	Normalizes micro- circulation, blood aggregation
Glipizid (Minidiab, Glucontrol, Antidiab)	5	20	8-12
3 rd generation drugs (mg)
Glimepirid (Amaryl)	1-4	4	24

- third generation: Glimepiride (Amaryl).

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:

1) patients with type 2 DM (over the age of 35 – 50 years) who do not suffer severe metabolic abnormalities (hyperglycemia), ketosis or hyperosmolality;

2) [duration of diabetes less than 15 years.]

Contraindications.

1) type 1 DM;

2) blood diseases;

3) acute infections, heart, cerebral diseases;

4) trauma, major;

5) pregnant diabetics or lactation;

6) III – IV stages of angiopathy (but Glurenorm can be used in patients chronic renal failure, because of gastrointestinal tract excretion);

7) coma and precoma.

Side effects.

1) hypoglycemia (hypoglycemic effect of sulfanilureas will be the most obvious in 7 – 12 days from the beginning of the treatment);

2) allergy;

3) influence on gastrointestinal tract (nausea and others);

4) leucopenia (decreasing of the quantity of white blood cells, platelets);

5) 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 include:

Metformine (Siofor), Adebit, Bufarmin.

Action: Video

1) inhibition of gastrointestinal glucose absorption;

2) decreasing of glyconeogenesis, lipogenesis;

3) enhancing glucose transport into muscle cells;

4) increasing the quantity of insulin’s receptors;

5) stimulation of anaerobic and partly aerobic glycolis;

6) anorrhexogenic effects.

Indications:

Obese patients with type 2 DM, with middle severity of the disease without ketosis.

Contraindications:

1) heart and lung disease with their insufficiency (chronic heart and lung failure);

2) status with hypoxemia;

3) acute and chronic liver and kidney diseases with decreased function;

4) pregnant diabetics, lactation;

5) old age;

6) alcoholism;

7) coma and precoma.

Side effects.

1) allergy;

2) gastrointestinal tract disorders;

3) lactoacidosis.

Alpha-glucosidase inhibitors

Acarbosa.

Action:

1) inhibition of gastrointestinal tract absorption (blocation of α-glucozidase);

2) lowering of pastprandial glucose level (postprandial “spikes” in blood glucose are increasingly implicated as a major cause of cardiovascular complications);

3) 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, diarrhea.

Non-sulfanylureas insulin stimulator

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 (16 mg/d)).

Nateglinid (Starlix 0,06; 0,12; 0,18).

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 and visual disturbances.

Thiozolidindiones

Rosiglitazon (Avandia, Rosinorm) Dose in 1 tabl. 0,002;0,004;0,008

Pioglitazon (Actos, Pionorm) Dose in 1 tabl. 0,015; 0,03; 0,045

Action of thiozolidindiones

- Agonist to the receptors of the nucleus PPARγ 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.

Combined preparates

Glibomet consists of Maninil 2,5 mg and Siofor 400 mg

Insulin

Insulin has been available for the treatment of patients with DM since 1921.

History of insulin discovery

In this lab, Banting and Best carried out early experiments which led to the discovery of insulin

In 1920, Canadian surgeon Frederick Banting visited the University of Toronto to speak to the newly appointed head of the department of physiology, John J.R. Macleod.. Macleod had studied glucose metabolism and diabetes, and Banting had a new idea on how to find not only the cause but a treatment for the so-called "sugar disease."

Frederick Banting (1891 - 1941)

John J.R. Macleod (1876 – 1936)

Late in the nineteenth century, scientists had realized there was a connection between the pancreas and diabetes. The connection was further narrowed down to the islets of Langerhans, a part of the pancreas. From 1910 to 1920, Oscar Minkowski and others tried unsuccessfully to find and extract the active ingredient from the islets of Langerhans. While reading a paper on the subject in 1920, Banting had an inspiration. He realized that the pancreas' digestive juice was destroying the islets of Langerhans hormone before it could be isolated. If he could stop the pancreas from working, but keep the islets of Langerhans going, he should be able to find the stuff! He presented this idea to Macleod, who at first scoffed at it. Banting badgered him until finally Macleod gave him lab space, 10 experimental dogs, and a medical student assistant.

In May, 1921, as Macleod took off for a holiday in his native Scotland, Banting and his assistant Charles Best began their experiments. By August they had the first conclusive results: when they gave the material extracted from the islets of Langerhans (called "insulin," from the Latin for "island") to diabetic dogs, their abnormally high blood sugars were lowered. Macleod, back from holiday, was still skeptical of the results and asked them to repeat the experiment several more times. They did, finding the results the same, but with problems due to the varying purity of their insulin extract.

Charles Best (1899 – 1978)

Macleod assigned chemist James Bertram Collip to the group to help with the purification. Within six weeks, he felt confident enough of the insulin he had isolated to try it on a human for the first time: a 14-year-old boy dying of diabetes. The injection indeed lowered his blood sugar and cleared his urine of sugars and other signs of the disease. Banting and Best published the first paper on their discovery a month later, in February, 1922. In 1923, the Nobel Prize was awarded to Banting and Macleod for the discovery, and each shared their portion of the prize money with the other researchers on the project.

James Bertram Collip

(1893 – 1965)

Leonard Tompson before and after insulintherapy

Ironically, Banting's original idea wasn't entirely correct. He and Best later found they could obtain insulin even from an intact pancreas. Improved technology for testing and detecting sugar in the blood and urine provided information that earlier researchers didn't have, and this encouraged them to pursue a line of thinking that may have looked like a dead end to those working in the decades before them.

The discovery of insulin was one of the most revolutionary moments in medicine. Though it took some time to work out proper dosages and to develop manufacturing processes to make enough insulin of consistent strength and purity, the introduction of insulin seemed literally like a miracle. One year the disease was an automatic death sentence; the next, people -- even children -- had hopes of living full and productive lives even with the disease. Estimates show there are more than 15 million diabetics living today who would have died at an early age without insulin.

For many years, the most commonly used preparations consisted of a combination of pancreatic bovine and porcine insulin. Contamination of small amounts (2 to % percent) 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) or yeast by recombinant DNA technology.

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	5 - 10 min.	0,5 – 2,5	3 - 4
Short-acting Video	Humodar R Actrapid HM Monodar R Actrapid MC Iletin	0,5 – 1,0	1 – 4	5 – 8
Intermediate-acting	Humodar B Protaphan HM Humulin L NPH Monotard MC	1 - 3	6 – 12	18 – 26
Long-acting Video 1 Video 2	Ultratard HM Ultralong	4 - 8	14 - 20	20 – 36
	Glargine (Lantus) Levemir	24 h
Combined preparations Video 1 Video 2	Humodar C-15 Mixtard 30 HM Monodar C-30	0,5	Depends on quantity of components

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 are available, and the major difference in their duration of action.

Only short-acting insulins should be given intravenously; all the types can be injected subcutaneously.

Insulin preparations.

Indications for insulin therapy

1. All patients with type I DM.

2. Some patients with type II 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 is more physiologic). 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.

Scheme: 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 dinner; 2/3 – 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.)

Insulin pump (Video) is very useful in achievement of glucemic control.

An insulin pump can help diabetic manage his diabetes. By using an insulin pump, he can match his insulin to his lifestyle, rather than getting an insulin injection and matching his life to how the insulin is working. When patient works closely with his diabetes care team, insulin pumps can help him keep his blood glucose levels within target ranges.  People of all ages with type 1 diabetes use insulin pumps and people with type 2 diabetes have started to use them as well.

How do insulin pumps work?

Insulin pumps deliver rapid- or short-acting insulin 24 hours a day through a catheter placed under the skin. Your insulin doses are separated into:

• Basal rates
• Bolus doses to cover carbohydrate in meals
• Correction or supplemental doses

Basal insulin is delivered continuously over 24 hours, and keeps the blood glucose levels in range between meals and overnight. Often, diabetic programs different amounts of insulin at different times of the day and night.

When patient east, he use buttons on the insulin pump to give additional insulin called a bolus. He takes a bolus to cover the carbohydrate in each meal or snack. If he eats more than he planned, he can simply program a larger bolus of insulin to cover it.

Patient also takes a bolus to treat high blood glucose levels. If he has high blood glucose levels before he eats, he gives a correction or supplemental bolus of insulin to bring it back to his target range.

Knowing how an insulin pump works is one thing. But patient may be wondering where he is supposed to put it. He can buy a pump case or it can be attached to a waistband, pocket, bra, garter belt, sock, or underwear. He can also tuck any excess tubing into the waistband of your underwear or pants.

When diabetic sleeps, he could try laying the pump next to you on the bed. He could even try wearing it on a waistband, armband, legband, or clip it to the blanket, sheet, pajamas, stuffed toy, or pillow with a belt clip.

Showering and bathing are other instances when patient should know where to put his insulin pump. Although insulin pumps are water resistant, they should not be set directly in the water. Instead, patient can disconnect it. All insulin pumps have a disconnect port for activities, such as swimming, bathing, or showering. Some pumps can be placed on the side of the tub, in a shower caddy, or in a soap tray. There are also special cases you can buy. Diabetic can hang these cases from your neck or from a shower curtain hook.

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 IDDM 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 use is recommended.

Future directions in improving glycemic control:

- nasal insulin preparations;

Inhaled insulins

Several reports describing research success with pulmonary insulins were presented. Inhaled insulin products in development include:

• Exubera by Inhale Therapeutics, Pfizer, and Aventis
• AERx by Aradigm and Novo Nordisk
• Insulin Technospheres by Mannkind/PDC
• AIR System by Alkermes with Eli Lilly
• Aerodose by Aerogen with Disetronic.

- 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.

Plant’s therapy (phytotherapy).

1) hypoglycemic action;

2) treatment of chronic diabetics complications;

3) influence on the immune reactivity.

Patient’s education.

Video (link for life)

Patient education is essential to ensure the effectiveness of the prescribed therapy, to recognize indications for seeking immediate medical attention, and to carry out appropriate foot care. On each physician visit, the patient should be assessed for symptoms and signs of complications, including a check of the feet and the pulses and sensation in the feet and legs, and a urine test for albumin. The serum creatinine levels should be assessed regularly (at least yearly) and an ECG and complete ophthalmologic evaluation should be performed at least yearly. Coexistent hypertension and hypercholesterolemia increases the risks for specific late complications and requires special attention and appropriate treatment.

Principles of education (Video)

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.

Video 1

Video 2

Treatment of long-term complications

The main principle: adequate metabolic control.

Diabetic retinopathy.

1) careful ophthalmologic examination (at least yearly) by ophthalmologist experienced with diabetes;

2) nonproliferative retinopathy:

- 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) preproliferative or proliferative retinopathy: treatment by photocoagulation.

Diabetic nephropathy.

1) low-protein diet (less than 40 g of protein daily);

2) inhibitors of ACF (renitec);

3) hypotensive therapy;

4) hemodyalisis, kidney’s transplantation.

Diabetic angiopathy of lower extremities.

1) patient education in foot care; early detection of risk factors, ulcers, infections, calluses, exposed nails, diminished pulses, deformities;

2) anticoagulants;

3) preparations for improvement blood circulation.

Diabetic neuropathy.

1) Treatments for neuropathy include preparations of α-lipoid acid (Berlition, Espa – lipon, Tiogama), inhibitors of aldose reductase (sorbinil), multivitamins, phenytoin, carbamazepin (Tegretol), amitriptyline, nootropil, piracetam;

2) physiotherapy (inductotermia, magnitolazerotherapy and others).

3) Specific treatment for few types of visceral neuropathy:

- Treatments for erectile dysfunction caused by nerve damage vary widely and range from oral pills, a vacuum pump, pellets placed in the urethra, and shots directly into the penis, to surgery. All these methods have strengths and drawbacks. Psychotherapy to reduce anxiety or address other issues may be necessary. Surgery to implant a device to aid in erection or to repair arteries is another option.

- Retrograde ejaculation caused by diabetes or surgery may be improved with a medication that improves the muscle tone of the bladder neck. A urologist experienced in infertility treatments may assist with techniques to promote fertility, such as collecting sperm from the urine and then using the sperm for artificial insemination.

- Treatment for neurogenic bladder depends on the specific problem and its cause. If the main problem is retention of urine in the bladder, treatment may involve medication to promote better bladder emptying and behavior changes to promote more efficient urination, called timed urination. Occasionally, people may need to periodically insert a thin tube called a catheter through the urethra into the bladder to drain the urine. Learning how to tell when the bladder is full and how to massage the lower abdomen to fully empty the bladder can help as well. If urinary leakage is the main problem, medications or surgery can help.

There are several specialized sanatoriums for diabetics in Truscavets, Myrgorod, Odessa.