Diabetes mellitus: etiology, pathogenesis, genetics, classification, diagnostic criteria. Classification, diagnostic criteria and treatment of diabetic angio– and neuropathy.

 

The pancreas is an elongated orgaestled next to the first part of the small intestine. Its gross anatomy and the structure of pancreatic exocrine tissue and ducts can be discussed in the context of the digestive system.

The endocrine pancreas refers to those cells within the pancreas that synthesize and secrete hormones.

The endocrine portion of the pancreas takes the form of many small clusters of cells called islets of Langerhans  or, more simply, islets. Humans have roughly one million islets. In standard histological sections of the pancreas, islets are seen as relatively pale-staining groups of cells embedded in a sea of darker-staining exocrine tissue.

Pancreatic islets house three major cell types, each of which produces a different endocrine product:

·   Alpha cells (A cells) secrete the hormone glucagon.

·   Beta cells (B cells) produce insulin  and are the most abundant of the islet cells.

Delta cells (D cells) secrete the hormone somatostatin, which is also produced by a number of other endocrine cells in the body.

Interestingly, the different cell types within an islet are not randomly distributed – beta cells occupy the central portion of the islet and are surrounded by a “rind” of alpha and delta cells. Aside from the insulin, glucagon and somatostatin, a number of other “minor” hormones have been identified as products of pancreatic islets cells.

Islets are richly vascularized, allowing their secreted hormones ready access to the circulation. Although islets comprise only 1-2% of the mass of the pancreas, they receive about 10 to 15% of the pancreatic blood flow. Additionally, they are innervated by parasympathetic and sympathetic neurons, and nervous signals clearly modulate secretion of insulin and glucagon.

The term Diabetes Mellitus refers to the excretion of large quantities of sweet urine. Diabetes is an old word for siphon and means “dieresis”, mellitus means “sweet”. The clinical syndrome known as DM comprises a wide variety of symptoms, physical findings and laboratory abnormalities, in which multiple etiologic factors are involved, the pathophysiology is partly understood and treatment is unsatisfactory. The hallmark of DM is hyperglycemia.

Diabetes Mellitus (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

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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 opf 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.

 

Etiology, pathogenesis and genetics of diabetes mellitus. Classification of diabetes mellitus.

 

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).

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Etiologic classification of  DM

I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

A. Immune mediated

B. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

III. Other specific types

A. Genetic defects of β-cell function

1. Chromosome 12, HNF-1_ (MODY3)

2. Chromosome 7, glucokinase (MODY2)

3. Chromosome 20, HNF-4_ (MODY1)

4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)

5. Chromosome 17, HNF-1_ (MODY5)

6. Chromosome 2, NeuroD1 (MODY6)

7. Mitochondrial DNA

8. Others

B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipoatrophic diabetes

5. Others

C. Diseases of the exocrine pancreas

1. Pancreatitis

2. Trauma/pancreatectomy

3. Neoplasia

4. Cystic fibrosis

5. Hemochromatosis

6. Fibrocalculous pancreatopathy

7. Others

D. Endocrinopathies

1. Acromegaly

2. Cushing’s syndrome

3. Glucagonoma

4. Pheochromocytoma

5. Hyperthyroidism

6. Somatostatinoma

7. Aldosteronoma

8. Others

E. Drug or chemical induced

1. Vacor

2. Pentamidine

3. Nicotinic acid

4. Glucocorticoids

5. Thyroid hormone

6. Diazoxide

7. b-adrenergic agonists

8. Thiazides

9. Dilantin

10. α-Interferon

11. Others

F. Infections

1. Congenital rubella

2. Cytomegalovirus

3. Others

G. Uncommon forms of immune-mediated diabetes

1. “Stiff-man” syndrome

2. Anti-insulin receptor antibodies

3. Others

H. Other genetic syndromes sometimes associated with diabetes

1. Down syndrome

2. Klinefelter syndrome

3. Turner syndrome

4. Wolfram syndrome

5. Friedreich ataxia

6. Huntington chorea

7. Laurence-Moon-Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10. Prader-Willi syndrome

11. Others

IV. Gestational diabetes mellitus

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.)

 

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

 

Stages of DM development

1. Prediabetes (risk factors or predispose factors):

–              Obesity (pict.);

                                                                                                          www.myfight.com

–              – 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. Categories of increased risk for DM (2010 ADA Guidelines):

                        HbA1c = 5.7 –6.4%

                        Fasting Glucose = 100-126 mg/dL

                        2hr OGTT = 140-200 mg/dL

Important to note that all 3 tests represent a continuous risk of developing diabetes that extends even below the lower limits.

                        Patients with A1c = 6-6.5% are considered to be at very high risk for developing diabetes:10 x more likely than those with A1c < 6.0%

4.                 3. Clinical manifestation of DM.

 

When should we screen for diabetes:

1.     All patients ≥ 45 years of age.

2.     All patients with BMI ≥ 25 kg/m2+any of the following:

2.1.                    Hypertension of ≥140/90 mmHg

2.2.                    HDL < 35 mg/dL, or Triglycerides > 250 mg/dL

2.3.                    Clinical insulin resistance (severe visceral obesity, acanthosisnigricans)

2.4.                    History of cardiovascular disease.

2.5.                    gestational DM, or delivered a baby > 9 lbs

2.6.                    African/Lationo/Native/Asian American or Pacific islander

2.7.                    First degree relative with diabetes

2.8.                    physically inactive

3.     If testing is normal, then repeat screening in 3 years.

Pathophysiology of DM

 

Clinical features and diagnosis of diabetes mellitus.

Signs and symptoms.

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The classic manifestation of type1 DM include :

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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.

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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 skiecrosis 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

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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 cao 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.

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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 iondiabetics.

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 oral glucose tolerance test (OGTT):

If the diagnosis is still in doubt, then perform an OGTT.

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.

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:

–        

–        

Also, oral GTT could be made from capillary blood samples.

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) but less rhan 6,1 mmol/l;

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).

Patients with IFG and/or IGT are now referred to as having ‘‘pre-diabetes’’ indicating the relatively high risk for development of diabetes in these patients •

• IFG and IGT may be associated with the metabolic syndrome,which includes obesity (especially abdominal or visceral obesity), dyslipidaemia of the hightriglyceride and/or low-HDL type, and hypertension.

• Individuals who meet criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near–normal glycated haemoglobin levels, and those with IGT may manifest hyperglycemia only when challenged with an OGTT.

Table – Criteria for the diagnosis of diabetes

1. HbA1C ≥6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*

OR

2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.*

OR

3. 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*

OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dl (11.1 mmol/l).

*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing.

 

3)    Serological markers of an autoimmune pathologic process in type 1 DM, including islet cell antibody, GAD, IA-2, IA- 2β, or insulin autoantibodies, are present in 85-90% of individuals when fasting hyperglycemia is detected

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);

 

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Sugar level fluctuates significantly throughout the 24 hours–dependent on intake and activities level, thus not a reliable measure of control using random testing. Glycosylated hemoglobin (A1C) is a by product of sugar metabolism and higher sugar over time=higher A1C. A1C testing is not dependent on fasting. It is an “average” measurement, thus more reliable.

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7)     acetonuria;

8)    blood lipids and others.

III. Instrumental investigations usually are used to diagnose chronic complications 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 g/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).

 

Long-term (late) complications of diabetes mellitus: 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.

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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.

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Pict. In the first few years of type 1 DM there is hyperfiltration which declines fairly steadily 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 iondiabetis 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. Different nerves are affected in different ways.

Sensorimotor polyneuropathy

 Longer nerve fibers are affected to a greater degree than shorter ones because nerve conduction velocity is slowed in proportion to the nerve length. In this case, decreased sensation and loss of reflexes occurs first in the toes of each foot, and then extends upward. Usually, this condition is described as glove-stocking distribution of numbness, sensory loss, dysesthesia and nighttime pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception, the sense of the limb in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk of developing ulcers and infections on the feet and legs, which can lead to amputation. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. The loss of motor function results in dorsiflexion, contractures of the toes, loss of the interosseous muscle function, and leads to contraction of the digits, so called hammer toes. These contractures occur not only in the foot but also in the hand, where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.

Autonomic neuropathy

 The autonomic nervous system is composed of nerves serving the heart, gastrointestinal system and genitourinary system. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension, or fainting when standing up. In case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain. This symptom is usually accompanied by the loss of the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy. Gastrointestinal tract manifestations include delayed gastric emptying, gastroparesis, nausea, bloating, and diarrhea. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia when an oral diabetic agent is taken before meal and does not get absorbed until hours or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small intestine can cause bacterial overgrowth, made worse by the presence of hyperglycemia. This leads to bloating, gas and diarrhea. Urinary symptoms include urinary frequency, urgency, incontinence, and retention. Again, because of urine retention, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, and reflux nephropathy.

Cranial neuropathy

When cranial nerves are affected, oculomotor (3rd) neuropathies are most common. The oculomotor nerve controls all of the muscles that move the eye, with the exception of the lateral rectus and superior oblique muscles. It also serves to constrict the pupil and open the eyelid. The onset of diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia. All of the oculomotor muscles innervated by the third nerve may be affected, except for those that control pupil size. This is because pupillary function within CNIII is found on the periphery of the nerve (in terms of a cross sectional view), which makes it less susceptible to ischemic damage (as it is closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but the fourth nerve, the trochlear nerve (that innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nerves can occur and lead to painful syndromes that mimic myocardial infarction, cholecystitis or appendicitis. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome

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

Ieurogenic 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 functioormally. 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.

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)    ACE- inhibitors ;

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.

Treatment of Diabetic peripheral neuropathy (DPN)  rests on a two-pronged approach: modification of the underlying disease and control of pain symptoms. Disease modification includes tight glycemic control, which in one study reduced the risk of development of clinical diabetic neuropathy in patients with insulin-dependent diabetes by as much as 62%. The maintenance of ideal body weight and normal lipid levels is also fundamental to the prevention of diabetic neuropathy. Recognition of the clinical symptomatology produced by the various pathogenic mechanisms described above will ultimately provide a logical basis for pain treatment selection. Intensive glucose control (HbA1c ≤7 mmol/L) with diabetic diet, peroral antidiabetic agents or insulin, particularly when instituted early in DM, delay or prevent clinically manifest DPN. There is still no cure for DPN, as pharmacotherapy can only treat the symptoms of DPN (Acta Clin Croat 2011; 50:289-302).

 

Antidepressants

 Tricyclic antidepressants (TCAs) are accepted choices ieuropathic conditions and a meta-analysis of randomized clinical trials indicated their efficacy in treating painful diabetic (DPN) and nondiabetic polyneuropathy. Antihyperalgesic effects of tricyclic antidepressants may be related to enhancement of noradrenergic descending inhibitory pathways and partial sodium channel blockade, mechanisms that are independent of their antidepressant effects. Starting doses of TCAs should be low and dosage should be titrated slowly until pain is adequately controlled or side effects limit continued titration. Some of the third-generation antidepressants, especially venlafaxine and duloxetine, have been shown to have comparable efficacy to the TCAs, but with a better side effect profile.

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that inhibits the reuptake of both serotonin and norepinephrine. It has demonstrated significantly greater pain relief compared with placebo in several randomized clinical trials (RCTs) in patients with DPN. The optimal dosage of duloxetine is 60 mg/day. Venlafaxine is an SSNRI that inhibits serotonin reuptake at lower dosages and both serotonin and norepinephrine reuptake at higher dosages. The efficacy dosage of venaflaxine is 150-225 mg/day. A 2- to 4-week period is often required to titrate to an effective dosage.

 

Anticonvulsants

 The anticonvulsant compounds are some of the best-studied drugs for neuropathic pain and there is substantial evidence for their efficacy based on metaanalyses and randomized clinical trials. Multiple RCTs have shown the efficacy of many of these drugs in a large variety of types of neuropathic pain. Unfortunately, complete relief of any form of neuropathic pain is only rarely achieved with the use of antiepileptic drugs. Usually, pain reduction by 50% is achieved in only one-half of treated patients21. Perhaps the most extensively studied agent is pregabalin, which has shown, in a large number of multicenter RCTs, clear efficacy in reducing pain and improving sleep in patients with postherpetic neuralgia and diabetic polyneuropathy. The effective dosage is 300-600 mg/day, administered in two to three divided doses. Improvement can be seen within days. Pregabalin is believed to exert its analgesic effect by binding to the α2 delta subunit of voltage-gated calcium channels on primary afferent nerves, and reducing the release of neurotransmitters from their central terminals. Multicenter RCTs have shown the efficacy of gabapentin at dosage of 900-3600 mg/day in the treatment of postherpetic neuralgia and diabetic polyneuropthy. Gabapentin is a GABA receptor agonist. The ability of the drug to block L-type voltage-dependent Ca2+ channels is the probable reason for its antiepileptic and analgesic properties. There is also evidence for the efficacy of topiramate, lamotrigine, carbamazepine and oxcarbamazepine in the treatment of different DPN conditions. Carbamazepine and perhaps oxcarbamazepine are used as first-line therapy for trigeminal neuralgia. Side effects of anticonvulsants Carbamazepine (CBZ) entails frequent adverse events, which include sedation, dizziness, and gait abnormalities. Liver enzymes, blood cells, platelets and sodium levels must be monitored for at least 1 year due to the possible risk of hepatitis-anaplastic effects or hyponatremia. Induction of microsomal enzyme systems may influence the metabolism of several drugs. In contrast to CBZ, oxcarbazepine (OXC) does not entail enzymatic induction and there is little risk of crossed cutaneous allergy. In the first months of treatment, sodium levels must be monitored because OXC, like CBZ, induces hyponatremia, particularly in the elderly (6% in a cohort of 54 patients). As regards other side effects, although better tolerance has been claimed with OXC compared with CBZ, this notion lacks consistent evidence from class I trials. In a recent trial in painful DPN, 27.5% of the OXC group discontinued treatment due to central or gastrointestinal side effects versus 8% on placebo. The most common side effects of gabapentin (GBP) and pregabalin include dizziness, somnolence, peripheral edema, and dry mouth, with a similar frequency for both drugs. Whilst GBP is widely accepted as highly tolerable even at high dosages (>2400 mg), the reports on pregabalin change remarkably with the daily dose: with 150 to 300 mg there is almost no difference from placebo, whilst the withdrawal rate reaches 20% with 600 mg. Lamotrigine is generally well tolerated. Side effects include dizziness, nausea, headache and fatigue. However, it may induce potentially severe allergic skin reactions. Lamotrigine should not be used in combination with valproate.

 

Opioids

 Opioids may be useful, especially in acute stage, but their use for chronic pain management remains somewhat controversial. A meta-analysis of intermediate term studies with opioids (up to eight weeks) showed a significant reduction in pain scale measurement for patients with DPN, comparable to results with maximal dose gabapentine. Patients are candidates for opioid therapy after all other appropriate therapies have failed. Opioids exert their analgesic effect through at least four groups of receptors. The distribution of these receptors throughout the body, along with their tissue densities withiumerous organ systems, account for the global and varied effects of these drugs. Opioids are available in a variety of preparations. In addition to common, PO, IM and IV route of administration, they may be given transdermally (fentanyl as buprenorphine patch), transmucosally (fentanyl oral), and intraspinally.

 

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in patients with musculoskeletal or joint abnormalities secondary to long-standing neuropathy; joint deformities may actually be the primary source of pain. Both ibuprofen (600 mg four times daily) and sulindac (200 mg twice daily) can lead to substantial pain relief in patients with diabetic neuropathy. There is a theoretical concern that NSAIDs may impair nerve circulation and worseerve injury due to inhibition of prostacyclin synthesis. Cautious use of this class of drugs is warranted until this possibility is fully evaluated.

 

Others

 Levodopa has been evaluated as the possible treatment in some cases of painful diabetic neuropathy (double-blind placebo-controlled study, 100 mg levodopa plus 25 mg benserazide to be taken three times per day for 28 days). The results seemed promising and levodopa may be a choice for pain control ieuropathy for which we do not have many alternative treatments. Some clinical studies have shown efficacy of dextromethorphan (400 mg/day) and memantine (55 or 35 mg/day) in the treatment of DPN. The mean reduction in pain intensity was 6% with dextromethorphan and 2% with memantine. In subjects who responded to dextromethorphan, there was a significant doseresponse effect on pain intensity (P=0.035). Selective approaches to pain-relevant N-methyl-d-aspartate receptors are warranted. Diabetic autonomic neuropathy is extremely difficult to treat, and the risks and adverse effects frequently outweigh the benefits of most pharmacological therapies. The symptoms may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, ACE inhibitors, and β-blockers. Gastroparesis may be improved with metoclopramide or erythromycin, but glycemic control is perhaps the best long-term treatment. Erectile dysfunction may respond to phosphodiesterase inhibitors, vacuum-constriction devices, and intracavernosal injections.

 

Nonspecific pharmacological treatment options

Alpha-lipoic acid One of the mechanisms implicated in the pathogenesis of diabetic neuropathy is increased oxidative stress. As a result, antioxidants have been studied for their potential to diminish oxidative stress, improve the underlying pathophysiology of neuropathy, and reduce pain. Based on data of randomized clinical trials, we suggest treatment with oral α-lipoic acid 600 mg once daily for patients with symptomatic painful diabetic polyneuropathy.

Acetyl-L-carnitine Acetyl-L-carnitine (ALC), the acetylated ester of the amino acid L-carnitine, has been evaluated in patients with diabetic peripheral neuropathy. According to data from two randomized controlled trials of identical design, an intention to treat analysis of 1257 DPN patients showed ALC 1000 mg (but not 500 mg) three times daily compared with placebo to be associated with significant improvement in pain scores in one of the studies and in the combined cohort. The benefit of ALC requires confirmation, particularly since significant improvement was not seen in both trials or at the lower dose of ALC.

Protein kinase C inhibition Elevated protein kinase C activity is thought to play a substantial role in the etiology of diabetic microvascular complications. Studies have been conducted using a protein kinase C-b inhibitor (LY333531). A preliminary study suggested the possibility of this agent to improve positive symptoms of allodynia and prickling pain. Large phase III multicenter clinical trials are in progress.

Aldose reductase inhibitors In addition to lowering blood glucose concentrations, another potential approach is to minimize the toxicity of hyperglycemia. To the degree that sorbitol accumulation might play a role in diabetic neuropathy, the use of an aldose reductase inhibitor to prevent sorbitol formation might be beneficial. In the studies reported thus far, there has usually beeo improvement in pain, an inconsistent effect on paresthesias, and an improvement ierve conduction in some but not all nerves.

Angiotensin converting enzyme inhibitors Angiotensin converting enzyme (ACE) inhibitors play a major role in the treatment of hypertension and in the prevention of progression of nephropathy in patients with diabetes. ACE inhibitors presumably act by inhibiting the production of angiotensin II, thereby lowering systemic and intraglomerular pressures. By mechanisms that are less clear, these drugs may also be beneficial in diabetic retinopathy and neuropathy.

Surgical decompression Surgical decompression of multiple peripheral nerves (called the Dellon procedure) is an alternative, controversial method for treating DPN. The purported rationale for surgical decompression is based on the notion that the metabolic stress of diabetes renders peripheral nerves susceptible to compressive injury at sites of potential nerve entrapment, and that compressive injury of multiple peripheral nerves is what leads to symptoms in most patients. While there is some experimental evidence that favors this hypothesis, other evidence to the contrary suggests that diabetes may partially prevent axonal injury by the development of resistance to axonal degeneration after nerve compression. In addition, there are no appropriately designed trials to support the use of surgical decompression of multiple peripheral nerves as a treatment for symptomatic DPN. Therefore, this treatment is not recommended.

 

Nonpharmacological treatment: Acupuncture, transcutaneous electrical nerve, laser therapy, mechanotherapy (massage), electrotherapy (galvanization, iontophoresis), ultrasound therapy, thermotherapy (cold and warm), hydro/balneotherapy and behavioral therapy (relaxation, biofeedback) have been tried. There is still no evidencebased treatment recommendations due to the lack of controlled studies in this field (level C).

 

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.

 

 

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

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

Video

References.

А. Main

1.                 Davidson’s Principles and Practice of Medicine (1st Edition) / Edited by N. R. Colledge,  B. R. Walker,  S. H. Ralston. – Philadelphia : Churchill Livingstone, 2010. – 1376 p.

2.                 Harrison’s Principles of Internal Medicine (18th edition) / D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J. Loscalzo,. – New York : McGraw-Hill Education – Europe, 2011. – 4012 p.

3.                 Kumar and Clark’s Clinical Medicine (8th Revised edition) (With studentconsult Online Access) / Edited by P. Kumar, M. L. Clark . – London : Elsevier Health Sciences, 2012. – 1304 p.

B. Additional

1. Greenspan’s Basic and Clinical Endocrinology ( 9th Revised edition) / David G. Gardner, Dolores M. Shoback. – New York : McGraw-Hill Education – Europe, 2011. – 880 p.

2. Oxford Textbook of Endocrinology and Diabetes 2nd Revised edition / Edited by John A. H. Wass, Paul Stewart, Stephanie A. Amiel [et al.]. – Oxford : Oxford University Press, 2011. – 2160 p.

3. Web-sites:

http://emedicine.medscape.com/endocrinology