Diabetes mellitus. Classification. Ethiology, pathogenesis, clinical pattern.

Principles of diagnostics and treatment of diabetes mellitus, I type.

Principles of diagnostics and treatment of diabetes mellitus, II type.

 

The pancreas is the most important intestinal gland. Pancreas lies in upper abdominal region behind the peritoneum (retroperitoneal position) at the level of the from 1st to 3d lumbar vertebrae. Along the upper margin of the pancreas runs the splenic artery. The right kidney and adrenal gland adjoin to body of pancreas. Anterior surface of gland touches the stomach, posterior surface – inferior vena cava and aorta. Tail adjoins to splenic hilus.

The endocrine pancreas is separate from the exocrine pancreas which is discussed under the gastrointestinal section. The endocrine pancreas is made up of small clumps of cells within the pancreas, called pancreatic islets, or the islets of Langerhans. These account for only 1% of the pancreatic mass. It is composed of three distinct cell types each producing a different hormone. The two important hormones are:  Glucagon (Secretion of glucagon is controlled by the level of blood sugar, being released when levels are too low. This greatly increases the output of sugar from the liver and returns blood sugar levels to normal.) and Insulin (Insulin is designed to lower blood sugar levels when they become too high and is released in periods when there is a lot of sugar available, like after a meal. A lack of insulin means the body has to use fat for metabolism rather than sugar and can lead to a condition known as ketoacidosis.)

 

Insulin is a peptide hormone, produced by beta cells of the pancreas, and is central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.

Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. With the exception of the metabolic disorder diabetes mellitus and metabolic syndrome, insulin is provided within the body in a constant proportion to remove excess glucose from the blood, which otherwise would be toxic. When blood glucose levels fall below a certain level, the body begins to use stored sugar as an energy source through glycogenolysis, which breaks down the glycogen stored in the liver and muscles into glucose, which can then be utilized as an energy source. As a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). In addition, it has several other anabolic effects throughout the body.

 

When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Patients with type 2 diabetes are often insulin resistant and, because of such resistance, may suffer from a “relative” insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan.

 

The human insulin protein is composed of 51 amino acids, and has a molecular weight of 5808 Da. It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds.

 

Insulin’s name is derived from the Latin insula for “island”. Insulin’s structure varies slightly between species of animals. Insulin from animal sources differs somewhat in “strength” (in carbohydrate metabolism control effects) in humans because of those variations. Porcine insulin is especially close to the human version.

Insulin was first isolated from the pancreas in 1922 by Banting and Best, and almost overnight the outlook for the severely diabetic patient changed from one of rapid decline and death to that of a nearly normal person.

Historically, insulin has been associated with “blood sugar,” and, true enough, insulin does have profound effects on carbohydrate metabolism. Yet, it is mainly abnormalities of fat metabolism, causing such conditions as acidosis and arteriosclerosis that are the usual causes of death of a diabetic patient. And, in patients with prolonged diabetes, the inability to synthesize proteins leads to wasting of the tissues as well as many cellular functional disorders. Therefore, it is clear that insulin affects fat and protein metabolism almost as much as it does carbohydrate metabolism.

Pancreas histology

 

EFFECT OF INSULIN ON CARBOHYDRATE METABOLISM

Immediately after a high carbohydrate meal, the glucose that is absorbed into the blood causes rapid secretion of insulin. The insulin in turn causes rapid uptake, storage, and use of glucose by almost all tissues of the body, but especially by the liver, muscles, and adipose tissue. One of the most important of all the effects of insulin is to cause most of the glucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen. Then, between meals, when food is not available and the blood glucose concentration begins to fall, the liver glycogen is split back into glucose, which is released back into the blood to keep the blood glucose concentration from falling too low.

The mechanism by which insulin causes glucose uptake and storage in the liver includes several almost simultaneous steps:

1. Insulin inhibits phosphorylase, the enzyme that causes liver glycogen to split into glucose. This obviously prevents breakdown of the glycogen that is already in the liver cells.

2. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It does this by increasing the activity of the enzyme glucokinase, which is the enzyme that causes the initial phosphorylation of glucose after it diffuses into the liver cells. Once phosphorylated, the glucose is trapped inside the liver cells, because phosphorylated glucose cannot diffuse back through the cell membrane.

3. Insulin also increases the activities of the enzymes that promote glycogen synthesis, including phosphofructokinase that causes the second stage in the phosphorylation of the glucose molecule and glycogen synthetase that is responsible for polymerization of the monosaccharide units to form the glycogen molecules.

Insulin also affects fat metabolism in ways that, in the long run, are perhaps equally as important. Especially dramatic is the long-term effect of insulin lack in causing extreme atherosclerosis, often leading to heart attacks, cerebral strokes, and other vascular accidents.

During the few hours following a meal when excess quantities of nutrients are available in the circulating blood, not only carbohydrates and fats but proteins as well are stored in the tissues; insulin is required for this to occur.:

1. Insulin causes active transport of many of the amino acids into the cells. Among the amino acids most strongly transported are valine, leucine, isoleucine, tyrosine, and phenylalanine. Thus, insulin shares with growth hormone the capability of increasing the uptake of amino acids into cells. However, the amino acids affected are not necessarily the same ones.

2 Insulin has a direct effect on the ribosomes to increase the translation of messenger RNA, thus forming new proteins. In some unexplained way, insulin “turns on” the ribosomal machinery. In the absence of insulin the ribosomes simply stop working, almost as if insulin operates an “on-off” mechanism.

3. Over a longer period of time insulin also increases the rate of transcription of DNA in the cell nuclei, thus forming increased quantities of RNA. Eventually, it also increases the rate of formation of new DNA and thus promotes reproduction of cells. All these effects promote still more protein synthesis.

4. Insulin also inhibits the catabolism of proteins, thus decreasing the rate of amino acid release from the cells, especially from the muscle cells. Presumably this results from some ability of the insulin to diminish the normal degradation of proteins by the cellular lysosomes.

5. In the liver, insulin depresses the rate of gluconeogenesis. It does this by decreasing the activity of the enzymes that promote gluconeogenesis. Since the substrates most used for synthesis of glucose by the process of gluconeogenesis are the plasma amino acids, this suppression of gluconeogenesis conserves the amino acids in the protein stores of the body.

 

Formerly, it was believed that insulin secretion is controlled almost entirely by the blood glucose concentration. However, as more has been learned about the metabolic functions of insulin for protein and fat metabolism, it has been learned that blood amino acids and other factors also play important roles in controlling insulin secretion.

 

Stimulation of Insulin Secretion by Blood Glucose. At the normal fasting level of blood glucose of 80 to 90 mg/dl, the rate of insulin secretion is minimal – in the order of 25 ng/min/kg (600 (xUnits/min/kg) of body weight. If the blood glucose concentration is suddenly increased to a level two to three times normal and is kept at this high level thereafter, insulin secretion increases markedly in two stages.

1. Insulin secretion increases almost tenfold within 3 to 5 minutes after acute elevation of the blood glucose; this results from immediate dump ing of preformed insulin from the beta cells of the islets of Langerhans. However, this initial high rate of secretion is not maintained; instead, it decreases about halfway back toward normal in another 5 to 10 minutes.

2. After about 15 minutes, insulin secretion rises a second time, reaching a new plateau in 2 to 3 hours, this time usually at a rate of secretion even greater than that in the initial phase. This secretion result both from additional release of preformed insulin and from activation of some enzyme system that synthesizes and releases new insulin from the cells.

Relationship between Blood Glucose Concentration and Insulin Secretion Rate. As the concentration of blood glucose rises above 100 mg/dl of blood, the rate of insulin secretion rises rapidly, reaching a peak some 10 to 30 times the basal level at blood glucose concentrations between 400 and 600 mg/dl. Thus, the increase in insulin secretion under a glucose stimulus is dramatic both in its rapidity and in the tremendous level of secretion achieved.

 

Diabetes Mellitus

Diabetes mellitus is characterized by metabolic disorders associated with absolute or relative deficiency of insulin production. Diabetes mellitus is a frequently occurring disease. People between the ages of 40 and 60 are mostly affected.

 

Diabetes can cause a cascade of medical problems that can lead to heart attacks, strokes and other medical problems.  In people with diabetes, their blood sugar stays too high, and sugar in those high levels is toxic. Over the years, that high blood sugar damages nerves and small and large blood vessels. Those problems can ultimately result in blindness, kidney failure, amputations, premature heart attacks and strokes.

Every 30 seconds, a leg is lost to diabetes somewhere in the world.  In fact, up to 70% of all leg amputations happen to people with diabetes.  In Malaysia itself, there are thousands of amputation cases a year.  About 85% of the amputees are diabetics. About 1.2 million Malaysians could be suffering from diabetic retinopathy, a common diabetic eye disease that can lead to blindness. At least 57% of Malaysians suffering from kidney diseases are also diabetic patients. There were about 15,000 patients in the country seeking haemodialysis treatment, with an average of 3,000 new kidney failure cases reported annually. In Malaysia, some 3.5 million people are diabetic. About 98% of diabetics here have Type 2 diabetes.

Diabetes can also have a major effect on disability and quality of life as people age.  According to a study in 2002, older women with diabetes were twice as likely as non-diabetic women to be unable to perform tasks such as walking a quarter of a mile, climbing 10 steps or cooking their own meals.

1 in 20 of the world’s adult populatioow has some form of diabetes. Diabetes struck 246 million people worldwide in 2006.  There were 6 diabetes deaths every minute in the world.

 

 An estimated 25% of the world’s nations have not made any specific provision for diabetes care iational health plans although the human and economic costs of diabetes could be significantly reduced by investing in prevention, particularly early detection to avoid the onset of diabetes complications.

There are 2 types of diabetes: Type 1 develops when insulin-producing cells in the pancreas — which help to regulate blood-sugar levels — have been destroyed.  Type 2 usually appears when the body no longer responds normally to its own insulin and/ or does not produce enough insulin.

         Type 1 diabetes is an autoimmune disease. An autoimmune disease results when the body’s system for fighting infection (the immune system) turns against a part of the body. In diabetes, the immune system attacks and destroys the insulin-producing beta cells in the pancreas. The pancreas then produces little or no insulin. A person who has Type 1 diabetes must take insulin daily to live.

 The most common form of diabetes is Type 2 diabetes. About 90-95% of people with diabetes have Type 2, according to American statistics. This form of diabetes is most often associated with older age, obesity, family history of diabetes, previous history of gestational diabetes, physical inactivity, and certain ethnicities.

 People who are overweight are particularly likely to develop Type 2 diabetes. However, Type 2 diabetes is increasingly being diagnosed in children and adolescents today.

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. 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.

Organic or functional affection of beta cells of the pancreas islets is the main factor in the pathogenesis of diabetes mellitus. This affection accounts for insufficient synthesis of insulin. Primary insufficiency of these cells can arise after infection, psychic trauma, removal of the pancreas, its destruction by a tumour, sclerosis of the pancreatic vessels, in pancreatitis, regular overeating; or insufficient in­take of substances required for the normal function of the insular ap­paratus. Familial predisposition (genetically determined functional insuffi­ciency of beta cells) is a background against which the diabetogenic effect of the named factors is realized.

Secondary insufficiency of beta cells can be due to endocrine dysfunc­tion: pituitary, adrenal and thyrfjid hyperfunction. Somatotropic and thyrotropic hormones, corticotropin, glucocorticoids and glucagon have diabetogenic properties and are called contrainsulin hormones. The pathogenesis of diabetes mellitus also depends on the presence of excess in­sulin inhibitor, i.e. enzyme insulinase (which is produced in the liver and is activated in the anterior pituitary hyperfunction) and also insulin an­tagonists and antibodies to insulin contained in the blood of patients.

Hyperglycaemia is a symptom of disordered carbohydrate metabolism. Increased blood sugar content is associated with a slowed glucose supply to the muscles and fatty tissue and its slow phosphorylation. This interferes with glucose decomposition, synthesis of glycogen, and conversion of carbohydrates into fats. High blood sugar depends also on intensified glucose supply from the liver to the blood and formation of glucose from glycogenic amino acids. Hyperglycaemia is usually attended by glycosuria, which in turn depends on an increased amount of glucose in the glomerular  filtrate and its complete reabsorption in the tubules. Upset protein metabblism is manifested by the inhibited synthesis of protein. Clinically it is manifested by formation of trophic ulcers and slow healing of wounds.

Disorders of fat metabolism are delayed formation of higher fatty acids and neutral fats from carbohydrates, and ample supply of free fatty acids to the blood. Clinically this is manifested by wasting of the patient. Fat infiltration of the liver is the sign of upset fat metabolism. A severe disorder in fat metabolism is ketosis. This is an accumulation in the blood of acetone bodies and ketones (/3-hydroxybutyric acid, acetoacetic acid, acetone) which are intermediate products of oxidation of higher fatty acids in the liver. Diabetic coma, a fatal complication of diabetes mellitus, can develop in this disorder of fat metabolism.

Polyuria, loss of sodium and partially of potassium are symptoms of upset water-salt metabolism in diabetes mellitus. The pathogenesis of polyuria is associated with glycosuria which elevates osmotic pressure in the tubules to decrease reabsorption of water. Reabsorption of sodium in the kidneys is also decreased.

A long-standing and incompletely compensated diabetes mellitus results in vascular changes (retinopathy, nephropathy, or Kimmelstiel-Wilson syndrome) and atherosclerosis. Pronounced fluctuations in the blood sugar increase pituitary activity, cause spastic atonia of the vessels, which, in turn, affects the structure of their walls, accelerates the destruc­tion of elastic fibres, and promotes sclerosis and calcinosis.

Insulin deficit inhibits phosphorylation of vitamin B₆ which often causes neuropathic complications of diabetes mellitus.

 

 

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).

 

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.);

·        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%

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.

Clinical features and diagnosis of diabetes mellitus.

Signs and symptoms.

The classic manifestation of type1 DM include :

The symptoms of diabetes mellitus are excessive thirst (polydipsia), increased appetite, polyuria, hyperglycaemia, glycosuria, wasting, weakness, decreased work capacity, and skin itching, especially in the perineal region.

 

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.

 

 

 

Risk factors in diabetes mellitus

 

Pathological anatomy. Diabetes mellitus is responsible for the decreased number of beta cells of the pancreatic islets, for their degranulation and hydropic degeneration. Hyaline and fat may be deposited in beta cells. This is not however a specific symptom of diabetes mellitus. At early stages of the disease, especially in young persons, morphological changes in these cells are absent.

 

Clinical picture.

The somatotype of type 2 diabetes

 

 

Inspection of the patient reveals rubeosis (reddening of the face, the cheeks, supraciliary arches, and the chin due to dilated cutaneous vessels) and xanthosis (yellowish decolouration of the palms and soles associated with upset conversion of carotin Into vitamin A in the liver and accumula of carotin in the skin).

 

 

Xanthosis

The patient’s skin is dry, rough, easily scaling, ivered with traces of scratching (due to skin itching). Furuncles, ex-tiatous and ulcerous lesions can also be found. At points of insulin injection, there are zones where fat is absent (insulin lipodystrophy).

 

 

Muscles and bones. Muscular atrophy and osteoporosis are observed in compensated diabetes mellitus. ‘Yoint limitations’ & ‘skin thickenings’ are the major typical signs in diabetes mellitus.

 

The ‘Preacher’s sign’: the hands of two patients with diabetes mellitus and the diabetic hand syndrome.

The patients are attempting to fully appose the palms and fingers.

The patient on the left illustrates moderate limitation. The patient on the right has significant impairment.

 

Cheiroarthropathy

Cardiovascular system. Atherosclerosis of various arteries with the corisponding clinical symptoms, angina pectoris, gangrene of the feet, etc. is ot infrequent.

 

Respiratory organs. Diabetes mellitus often concurs with bronchitis, pneumonia, and pulmonary tuberculosis.

Gastro-intestinal tract. Mouth mucosa and the tongue are dry. Paradontosis and pyorrhoea frequently occur. Appetite is very good and ometimes voracious (bulimia). Study of the gastric juice reveals the resence of hypo- or achlorhydria. Fat dystrophy of the liver and its cirhosis develop in some patients with long-standing decompensated diabetes mellitus.

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.

Diabetic nephropathy. Pyelonephritis s not infrequent. Arteriolosclerosis of the kidneys and intracapillary glomerulosclerosis (Kimmelstiel-Wilson syndrome) may occur. 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.

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:

Ø decreased GFR;

Ø blood hypertension;

Ø increased serum creatinine;

Ø signs of intoxication.

End-Stage Renal Disease Is a Serious Complication of Diabetes. Kidney disease is a known complication of diabetes. Diabetic kidney disease occurs in 20 and 40 percent of patients with diabetes and is the leading cause of End Stage Renal

Disease (ESRD).  Diabetic nephropathy is the leading cause of renal failure. It is defined by proteinuria > 500 mg in 24 hours in the setting of diabetes, but this is preceded by lower degrees of proteinuria, or “microalbuminuria.” Microalbuminuria is defined as albumin excretion of 30-299 mg/24 hours. Without intervention, diabetic patients with microalbuminuria typically progress to proteinuria and overt diabetic nephropathy. This progression occurs in both type 1 and type 2 diabetes.

As many as 7% of patients with type 2 diabetes may already have microalbuminuria at the time they are diagnosed with diabetes. In the European Diabetes Prospective Complications Study, the cumulative incidence of microalbuminuria in patients with type 1 diabetes was ∼ 12% during a period of 7 years. In the UKPDS, the incidence of microalbuminuria was 2% per year in patients with type 2 diabetes, and the 10-year prevalence after diagnosis was 25%.

The pathological changes to the kidney include increased glomerular basement membrane thickness, microaneurysm formation, mesangial nodule formation (Kimmelsteil-Wilson bodies), and other changes. The underlying mechanism of injury may also involve some or all of the same mechanisms as diabetic retinopathy.

Screening for diabetic nephropathy or microalbuminuria may be accomplished by either a 24-hour urine collection or a spot urine measurement of microalbumin. Measurement of the microalbumin-to-creatinine ratio may help account for concentration or dilution of urine, and spot measurements are more convenient for patients than 24-hour urine collections. It is important to note that falsely elevated urine protein levels may be produced by conditions such as urinary tract infections, exercise, and hematuria.

Initial treatment of diabetic nephropathy, as of other complications of diabetes, is prevention. Like other microvascular complications of diabetes, there are strong associations between glucose control (as measured by hemoglobin A1c [A1C]) and the risk of developing diabetic nephropathy. Patients should be treated to the lowest safe glucose level that can be obtained to prevent or control diabetic nephropathy. Treatment with angiotensin-converting enzyme (ACE) inhibitors has not been shown to prevent the development of microalbuminuria in patients with type 1 diabetes but has been shown to decrease the risk of developing nephropathy and cardiovascular events in patients with type 2 diabetes.

In addition to aggressive treatment of elevated blood glucose, patients with diabetic nephropathy benefit from treatment with antihypertensive drugs. Renin-angiotensin system blockade has additional benefits beyond the simple blood pressure-lowering effect in patients with diabetic nephropathy. Several studies have demonstrated renoprotective effects of treatment with ACE inhibitors and antiotensin receptor blockers (ARBs), which appear to be present independent of their blood pressure-lowering effects, possibly because of decreasing intraglomerular pressure. Both ACE inhibitors and ARBs have been shown to decrease the risk of progression to macroalbuminuria in patients with microalbuminuria by as much as 60-70%. These drugs are recommended as the first-line pharmacological treatment of microalbuminuria, even in patients without hypertension.

Similarly, patients with macroalbuminuria benefit from control of hypertension. Hypertension control in patients with macroalbuminuria from diabetic kidney disease slows decline in glomerular filtration rate (GFR). Treatment with ACE inhibitors or ARBs has been shown to further decrease the risk of progression of kidney disease, also independent of the blood pressure-lowering effect.

Combination treatment with an ACE inhibitor and an ARB has been shown to have additional renoprotective effects. It should be noted that patients treated with these drugs (especially in combination) may experience an initial increase in creatinine and must be monitored for hyperkalemia. Considerable increase in creatinine after initiation of these agents should prompt an evaluation for renal artery stenosis.

Retinopathy. Retinopathy in diabetes mellitus is manifested by the jresence of exudate in the retina, haemorrhages, and pigment abnormality n the yellow spot. Cataracts often occur.

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

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

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

        IV.            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).

Diabetic retinopathy is retinopathy (damage to the retina) caused by complications of diabetes mellitus, which can eventually lead to blindness. This is a degenerative condition where high blood sugar causes damage to the small blood vessels in the eye, which can bleed, leek fluid and cause deposits in the retina. It is an ocular manifestation of systemic disease which affects up to 80% of all patients who have diabetes for 10 years or more.

Diabetic retinopathy is the most common and most serious eye-related complication of diabetes. It is a progressive disease that causes retinal swelling and destroys small blood vessels in the retina, eventually leading to vision problems. In its most advanced forms, known as “diabetic macular edema” and “proliferative retinopathy,” it can cause moderate to severe vision loss and blindness.

Almost everyone with diabetes will develop a mild form of retinopathy involving damage to existing blood vessels within the eye. But vision loss only tends to occur with more advanced retinopathy. Reduced vision is caused by two mechanisms: the first by the growth of new, very delicate blood vessels, which tend to haemorrhage into the eye, blocking vision, and the second by leakage and bleeding into the retina.

Over time, the disease progresses to its advanced or proliferative stage, and fragile new blood vessels grow along the retina.

However, these fragile vessels can hemorrhage easily, and blood may leak into the retina and the clear, gel-like vitreous that fills inside of the eye. Unless quickly treated, this can result in spots, floaters, flashes, blurred vision, vision loss, and even temporary blindness. In later phases of the disease, continued abnormal vessel growth and the formation of scar tissue may cause serious problems such as retinal detachment and glaucoma, both of which can cause permanent blindness. Diabetic macular edema, which involves swelling in the retina that transiently or permanently impairs vision, can occur at any stage of diabetic retinopathy. Treatment to prevent or reverse this condition remains a major unmet clinical need.

CATARACTS

 

Though cataracts are common in ages 55+, people with diabetes are twice as likely to develop a cataract. This is a result of accelerated damage created in a high blood sugar environment – a process compounded by the normal stress of ageing if you are diabetic. Cataracts are also linked to leakage of calcium and sodium through damaged cell membranes and oxidative damage in the lens.

For those with type 1 diabetes, a diabetic-specific cataract can develop called the ‘sugar cataract’. This type occurs at any age, but most commonly in young adults in their 20s who are in very poor control of their condition. Blood sugar control can prevent this serious development so utmost care should be taken to follow all precautions if you have diabetes. If  develop a cataract, it caearly always be treated. Surgical procedures can involve removing the lens of an eye and implanting a new one – a move that sounds scary but these days is commonplace and highly successful.

Normal vision

The impact of advanced diabetic retinopathy on your vision

The impact of advanced cataracts on your vision

 

Changes in the nervous system. Polyneuritis is frequent. Headache, deranged sleep, and decreased work capacity are the symptoms of affection of the central nervous system.

Diabetic neuropathy is recognized by the American Diabetes Association (ADA) as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. As with other microvascular complications, risk of developing diabetic neuropathy is proportional to both the magnitude and duration of hyperglycemia, and some individuals may possess genetic attributes that affect their predisposition to developing such complications.

 

The precise nature of injury to the peripheral nerves from hyperglycemia is not known but likely is related to mechanisms such as polyol accumulation, injury from AGEs, and oxidative stress. Peripheral neuropathy in diabetes may manifest in several different forms, including sensory, focal/multifocal, and autonomic neuropathies.

 

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

More than 80% of amputations occur after foot ulceration or injury, which can result from diabetic neuropathy. Because of the considerable morbidity and mortality that can result from diabetic neuropathy, it is important for clinicians to understand its manifestations, prevention, and treatment.

Peripheral Neuropathy Symptoms

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.).

Peripheral neuropathy affects the nerves in the hands and legs. Peripheral neuropathy may affect the feet and legs before getting to the hands and arms. Symptoms of this condition include numbness or reduced sensation, particularly in the feet and toes; pain when walking; a burning or tingling feeling; and difficulty walking.

Chronic sensorimotor distal symmetric polyneuropathy is the most common form of neuropathy in diabetes. The most common symptoms of neuropathy are tingling, burning, “electrical” pain and but sometimes they may experience simple numbness, other unpleasant sensations or a loss of sensation. In patients who experience pain, it may be worse at night. Patients with simple numbness can present with a painless foot ulceration, so it is important to realize that lack of symptoms does not rule out presence of neuropathy. Physical examination reveals sensory loss to light touch, vibration, and temperature. Abnormalities in more than one test of peripheral sensation are > 87% sensitive in detecting the presence of neuropathy. Patients also typically experience loss of ankle reflex. Patients who have lost 10-g monofilament sensation are at considerably elevated risk for developing foot ulceration.

Pure sensory neuropathy is relatively rare and associated with periods of poor glycemic control or considerable fluctuation in diabetes control. It is characterized by isolated sensory findings without signs of motor neuropathy. Symptoms are typically most prominent at night.

Proximal Neuropathy Symptoms

Proximal neuropathy is another type of diabetic neuropathy. The National Institute of Diabetes and Digestive and Kidney Diseases reports that it typically affects older diabetic patients and those who suffer from type 2 diabetes. Symptoms of this kind of neuropathy usually occurs on one side of the body but may spread to the other side. Nerves close to the hips and shoulders are affected in this condition with symptoms such as needing help to go from a sitting to a standing position, unintentional weight loss, weakness in the legs, and pain in the hip, buttock or thigh.

Mononeuropathies typically have a more sudden onset and involve virtually any nerve, but most commonly the median, ulnar, and radial nerves are affected. Cranial neuropathies have been described but are rare. It should be noted that nerve entrapment occurs frequently in the setting of diabetes. Electrophysiological evaluation in diabetic neuropathy demonstrates decreases in both amplitude of nerve impulse and conduction but may be useful in identifying the location of nerve entrapment. Diabetic amyotrophy may be a manifestation of diabetic mononeuropathy and is characterized by severe pain and muscle weakness and atrophy, usually in large thigh muscles.

Several other forms of neuropathy may mimic the findings in diabetic sensory neuropathy and mononeuropathy. Chronic inflammatory polyneuropathy, vitamin B12 deficiency, hypothyroidism, and uremia should be ruled out in the process of evaluating diabetic peripheral neuropathy.

Autonomic Neuropathy Symptoms

The heart, lungs, sex organs, stomach, intestines and eyes are all controlled by the autonomic nervous system. The National Institute of Neurological Disorders and Stroke explains that diabetes affects the nerves that control these organs. This type of neuropathy is called autonomic neuropathy, and its signs are slow stomach emptying, erectile dysfunction in men, constipation, urinary incontinence, lightheadedness due to drops in blood pressure, increased heart rate when a person is at rest and not knowing that blood sugar levels are low.

Diabetic autonomic neuropathy also causes significant morbidity and even mortality in patients with diabetes. Neurological dysfunction may occur in most organ systems and can by manifest by gastroparesis, constipation, diarrhea, anhidrosis, bladder dysfunction, erectile dysfunction, exercise intolerance, resting tachycardia, silent ischemia, and even sudden cardiac death. Cardiovascular autonomic dysfunction is associated with increased risk of silent myocardial ischemia and mortality.

Focal Neuropathy. Focal neuropathy is also referred to as mononeuropathy and affects one particular nerve. It usually affects the nerves in the head, legs and arms. This form of diabetic neuropathy is painful, unpredictable and happens suddenly. However, it does not cause any long term damage and is typically seen in older adults. Symptoms of focal neuropathy depend on which nerve is involved and they may include bells palsy–paralysis on one side of the face, having difficulties focusing one eye, having aches behind one eye, pain in the frontal area of the thigh and chest pain.

People with diabetes also can suffer from neuropathy in parts of the body other than the feet. Nerve damage can lead to problems with digestive, bladder, bowel or sexual function. This is from damage to the autonomic nerves, which control such things as heart rate, blood pressure, digestion, sweating and erections. Such damage can cause a variety of unpleasant effects:

Bowel disturbances. Eating more fiber may correct bowel disturbances. If your stomach empties too slowly, a medication such as metoclopramide (Reglan) may help. For diarrhea, try an antidiarrheal drug such as loperamide (Imodium).

Erectile dysfunction. Drugs such as sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) may help. Vacuum devices or surgical implants are also options.

Bladder problems. Go to the bathroom every few hours rather than waiting until you feel the urge. If this doesn’t help, ask your doctor about drugs or surgery.

Dizziness. If standing up quickly brings on lightheadedness, take more time to change positions. Cutting out alcohol, wearing support stockings and increasing your dietary salt intake may also help.

Tingling, burning, unpleasant sensations. Several types of medicine can greatly reduce these symptoms, including tricyclic drugs and certain anticonvulsants. Most of my patients with diabetic neuropathy have gotten good relief from them.

There is no specific treatment of diabetic neuropathy, although many drugs are available to treat its symptoms. The primary goal of therapy is to control symptoms and prevent worsening of neuropathy through improved glycemic control. Some studies have suggested that control of hyperglycemia and avoidance of glycemic excursions may improve symptoms of peripheral neuropathy. Amitriptyline, imiprimine, paroxetine, citalopram, gabapentin, pregablin, carbamazepine, topiramate, duloxetine, tramadol, and oxycodone have all been used to treat painful symptoms, but only duloxetine and pregablin possess official indications for the treatment of painful peripheral diabetic neuropathy.16 Treatment with some of these medications may be limited by side effects of the medication, and no single drug is universally effective. Treatment of autonomic neuropathy is targeted toward the organ system that is affected, but also includes optimization of glycemic control.

 

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).

 

Diagnosis of diabetes

The main laboratory methods used to diagnose diabetes mellitus and assess its gravity are based on determination of sugar and ketone bodies in the urine, determination of sugar in the blood on a fasting stomach and  during the day, and glucose tolerance tests.

When a patient suspected for diabetes mellitus is examined, his blood and urine are in the first instance tested for sugar. Sugar in the urine of a diabetes mellitus patient may be 5-8 per cent and more. Morning urine of patients with latent diabetes mellitus may be free from sugar, and daily urine should therefore be better studied. Urine taken after giving the pa­tient a test meal or sugar can also be studied.

Blood of a healthy individual (with a fasting stomach) contains4.4~6.6 mmol/1 (80-120 mg/100 ml) of glucose. This concentration increases to 28-44 mmol/1 (500-800 mg/100 ml) and more in diabetes mellitus pa­tients.

 But in the mild forms of the disease the blood sugar may remain normal (especially so if the test is done on a fasting stomach). In such cases blood sugar should be determined 3 or 4 times a day with a normal diet given. If glycaemia appears to exceed normal in repeated glucose tolerance tests, the diagnosis of diabetes mellitus can be considered proved.

 After determining blood sugar on a fasting stomach, the patient is given to drink 70 g of glucose in 200 ml of water. Blood specimens are then taken at 30-minute intervals for 3 hours. The blood sugar in a healthy individual increases by about 50 per cent (but not over 9.4 mmol/1 or 170 mg/100 ml) during the first hour, while during the second hour the initial blood level is restored (or it may drop below (normal). The rise in the blood sugar is higher in diabetes mellitus patients, the increase in sugar concentration is delayed, while the initial level is not restored even in three hours. There is a variant of the glucose tolerance test in which another portion of glucose is given to the patient in one hour following the first dose. The first glucose dose intensifies the secretion of insulin in healthy persons, and the second dose does not therefore increase the sugar concentration in the blood, while sugar cuiw of diabetes mellitus patients gives another ascent (two-peak curve).

Glucose oxidase and Samogyi-Nelson tests are now used for determin­ing blood sugar. The glucose oxidase method is used to determine true glucose of the blood and it is therefore most specific, but the normal glucose level is slightly underestimated compared with the Hagerdon and Jensen method (3.3-5.5 mmol/1, or 60-100 mg/100 ml). The sugar con­centration in the blood depends also on the technique by which the blood specimen is taken: glucose level is higher in capillary than in the venous blood. Increased blood sugar does not always indicate diabetes mellitus since it may be the result of emotional excitation. Glucosuria is an indirect sign of hyperglycaemia. The presence of sugar in the urine in the absence of hyperglycaemia cannot be used as an evidence of diabetes mellitus either, since glucosuria can be due to decreased sugar permeability of the kidneys (renal threshold). In the presence of kidney pathology (nephrosclerosis), glucosuria may be absent even when the blood sugar is abnormally high.

Tests for urine sugar are qualitative and quantitative. Sugar can be determined in the urine by special indicator papers (glucotest) and tablets (for rapid determination of urine sugar). Determination of acetone and acetoacetic acid (acetone bodies) is obligatory. It should however be remembered that acetonuria can occur also in healthy individuals during fasting and in toxaemia of pregnancy.

Patients with clear signs of diabetes mellitus do not require glucose tolerance testing. Prednisolone or corticoglucose test should be carried out in persons predisposed to diabetes mellitus and with normal results of glucose tolerance test. The results of glucose tolerance test depend on various factors: fasting, pathological processes in the liver parenchyma,  juries, infections, acute disorders in cerebral circulation, and strong emotions.

Determination of the alkali reserve of the blood helps predict the approaching grave complication of diabetes mellitus, i.e. diabetic coma. The alkali reserve decreases sharply in moderate acidosis. It decreases not only in diabetes mellitus but also in acidosis of other aetiology, e.g. in fasting or in kidney diseases.

Course. The onset of the disease may be acute or gradual. The first signs of diabetes mellitus may be persistent itching and furunculosis. By the course and severity of the symptoms, and also by the body response to the therapy given, the clinical picture of diabetes mellitus is differentiated into light, moderate, and grave. The degree of hyperglycaemia, glycosuria, the presence of ketone bodies in the urine, and the gravity of acidosis should also be taken into consideration. In addition to the mentioned forms of diabetes mellitus, the following three stages are distinguished in its course: prediabetes, masked diabetes, and true diabetes mellitus. Prediabetes cannot be diagnosed by the existing methods. This can be defined as hereditary predisposition, obesity, and cases where newborns (both dead and alive) weigh over 4.5 kg. Masked diabetes mellitus can be detected by the glucose tolerance test. True diabetes mellitus is diagnosed by clinico-laboratory findings.

Diabetic coma is a grave and sometimes fatal complication of diabetes mellitus. It occurs if diabetes mellitus is treated improperly or if the disease is complicated by acute infections, injuries, or nervous stress. Toxic symp­toms develop gradually in most cases and the onset of coma is preceded by its precursors (precomatose state). Excessive thirst develops along with polyuria, epigastric pain, dyspepsia, headache, and loss of appetite. The patient’s breath smells of acetone (odour of rotten apples). Precomatose state is followed by the first phase of coma which is characterized (in addi­tion to the mentioned symptoms which are gradually intensified) by a strong nervous excitement: insomnia, restlessness, clonic convulsions, and Kussmaul’s respiration. The excitement is followed by a marked inhibition, the second phase of diabetic coma: the parent develops dizziness, shows no interest in surroundings, and finally loses) consciousness. When in a deep coma, the patient is motionless, the face may be pink or pallid, the skin dry, the muscle tone and tendon reflexes are decreased, pathological reflexes sometimes develop, the eyeball tone decreases, the eyeballs are soft to the touch, the pupils are narrow. Kussmaul’s respiration is heard at a considerable distance. The pulse is low and fast; the arterial pressure falls.  Hypothermia,  oliguria,  and sometimes anuria develop.  Blood sugar  markedly  increases   (from  22  to   55 mmol/1  or   from  400  to 1000 mg/100 ml). The alkali reserve of blood decreases to 15-30 per cent (v/v), the number of ketone bodies increases along with increased content of non-protein (residual) nitrogen; the chloride content decreases. Leucocytosis in coma can be as high as 50 x 10⁹ per 1 1 of blood with a neutrophilic shift to the left. Ketone bodies and considerable amounts of sugar are found in the urine. But gradual development of diabetic coma and distinct stages of this process are not always observed, and the terminal phase3f diabetic coma may come suddenly, without precursors.

The pathogenesis of diabetic coma is associated with acidosis mainly on account of accumulation of ketone bodies and their toxic effect on the central nervous system.

Hypoglycaemic coma arises in patients treated with insulin for diabetes mellitus, if their diet lacks carbohydrates or as a result of insulin over­dosage.

Hypoglycaemic coma develops rapidly, sometimes within a few minutes. Coma is preceded by a sudden feeling of hunger, weakness, sweating, tremor in the entire body, psychic and motor excitement. Com­atose state is characterized by pallor and moist skin, increased muscular tone and tendon reflexes, and convulsions; the pupils are dilated, the eyeballs remain firm. The blood sugar is low; sugar and acetone are absent from the urine. The patient quickly responds to treatment: after an intravenous infusion of a hypertonic solution of glucose, the patient quickly regains consciousness.

 

The main principles of Diabetes Mellitus therapy

 

1.     The major goal in treating diabetes is 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).

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.

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. Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes.

 

Drug classes used for the treatment of type 2 diabetes include the following:

1.       Biguanides

2.       Sulfonylureas

3.       Meglitinide derivatives (nonsulfonylurea secretagogues)

4. Alpha-glucosidase inhibitors

5. Thiazolidinediones (TZDs)

6. Glucagonlike peptide–1 (GLP-1) agonists

7. Dipeptidyl peptidase IV (DPP-4) inhibitors

8. Insulins

9. Amylinomimetics (Amylin agonist analogues)

10. Bile acid sequestrants

11. Dopamine agonists

 

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

Sulfanilureas include:

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

2.     second generation: Glibenclamide (Maninil), Glipizide (Glurenorm), Gliquidone;

 

3.     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.)

6)    Biguanides include:

 

Metformin (Siofor), Adebit, Buformin.

 

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)).

Nateglinide (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.

 

Thiazolidinediones

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 thiazolidinediones

–         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 thiazolidinediones usage

–         DM type 2, when diet and exercises are no effective;

–         Using with sulfanilureas, biguanides, insulin in case of their insufficient efficacy

Contraindications to thiazolidinediones 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 thiazolidinediones

–         Hypoglycemic conditions (rarely);

–         Peripheral edema;

–         Anemia;

–         Obesity.

 

GLP-1

Incretin Physiology

Main mechanism of action:

1. Augmentation of pancreas response (i.e. increases insulin secretion) in response to eating meals;

2. Suppression of pancreatic release of glucagon in response to eating;

3. Slowing down gastric emptying;

4. Reducing appetite, promote satiety via hypothalamic receptors;

5. Reducing liver fat content;

Exenatide injectable solution (Byetta)

 Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who have not achieved glycemic control with metformin or a sulfonylurea. The solution is administered by subcutaneous injection twice daily.

 

 

Treatment algorithm of Type 2 Diabetes

ADA/EASD Consensus Algorithm for the Management of Type 2 Diabetes

Reinforce lifestyle interventions at every visit. Check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%.

Summary of the tier 1 and tier 2 algorithms

Tier 1: These interventions represent the best-established and most effective and cost-effective therapeutic strategy for achieving the target glycemic goals.

Step 1: Lifestyle intervention should be initiated as a first step because of the numerous short- and long-term benefits that accrue from exercise and weight loss. Metformin should be initiated concurrently because of its glycemic effects, absence of weight gain or hypoglycemia, tolerability, and low cost.

Step 2: Another medication should be added to achieve glycemic goals if step 1 fails.

Step 3: Insulin therapy should be started or intensified if glycemic goals have not been reached.

Tier 2: In selected clinical settings, the second-tier algorithm may be considered.

When hypoglycemia is particularly undesirable, the addition of a GLP-1 agonist or pioglitazone to step 1 may be considered. If promotion of weight loss is a major consideration and the A1C level is close to target (<8%), a GLP-1 agonist is an option. A sulfonylurea may be added to these interventions if necessary. Further adjustments should be made if A1C target is not achieved.

For more information, read the full ADA/EASD consensus statement for the medical management of hyperglycemia in type 2 diabetes.

 

Insulin therapy of diabetes mellitus

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

For many years, the most commonly used preparations consisted of a combination of pancreatic bovine and porcine insulin. Contamination of small amounts (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.

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.

Step 1: Estimate Total Daily Insulin (TDI)

–         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.

 

Step 2: Select Type of Insulin Therapy

–         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.

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.

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

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;