Diabetes mellitus: etiology, pathogtnesis, classification, diagnostic criteria.

It is probably fair to state that about 2 to 4 percentage of the world population is affected with DM. The disease is more common in persons after age 45, in obese individuals, in certain ethnic groups, and in those with a positive family history of DM. The term DM 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. 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 secreted by - cells of islets of Langerhans of pancreatic gland.

Pancreatic islets have three major cell types, each of which produces a different endocrine product.

Hormones of pancreatic gland

Type of cells
G

Quantity of cells (%)

20 25 75 80 5 15 5 - 10

Secreted hormone
glucagon insulin somatostatin gastrin pancreatic polypeptide

The action of insulin Insulin is an anabolic hormone (promotes the synthesis of carbohydrates, proteins, lipids and nucleic acids). The most important target organs for insulin action are: the liver, muscle and adipocytes. The brain and blood cells are unresponsive to insulin.

The effects of insulin on carbohydrate metabolism include: 1) stimulation of glucose transport across muscle and adipose cell membranes; 2) regulation of hepatic glycogen synthesis; 3) inhibition of glucose formation from glycogen (glycogenolysis) and from aminoacid precursors (glyconeogenesis). The result of these actions is a reduction in blood glucose concentration. Protein metabolism:

1) the transfer of amino acids across plasma membranes; 2) stimulation of protein synthesis; 3) inhibition of proteolysis. Lipid metabolism: 1) incorporation of fatty acids from circulating triglyceride into adipose triglyceride; 2) stimulation of lipid synthesis; 3) inhibition of lipolisis. Nucleic acids metabolism: 1) stimulation of nucleic acid synthesis by stimulating the formation of adenosine triphosphate (ATP), DNA and RNF. Other effects: 1) stimulation of the intracellular flew of potassium, phosphate and magnesium in the heart; 2) inhibition of inotropic and chronoropic action (unrelated to hypoglycemia).

Type 1, or insulin-dependent diabetes mellitus (IDDM) 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.

Pathogenesis of type 1 DM

Current formulation of the pathogenesis (Video) of type 1 DM includes the following: 1. A genetic predisposition, conferred by diabetogenic genes on the short arm of chromosome C, either as part of it or in close proximity to the major histocompatibility complex (MMHC) region (more than 95 % of type 1 diabetes individuals are HLA DR3, DR4 or DR3/DR4; on the other hand, HLA DR2 confers protection against the development of type 1 DM); 2. Putative environmental triggers (possibly viral infections (Coxsackie B, rubella) or chemical toxins (nitrosourea compounds)) that in genetically susceptible individuals might play a role in initiating the disease process. 3. An immune mechanism gone awry, either initiation of immune destruction or loss of tolerance, leading to slow, progressive loss of pancreatic islet beta cells and eventual clinical onset of type 1 diabetes. Type 2 or non-insulin-dependent DM (NIDDM) is the most common form of diabetes, accounting for 95 90 % of the diabetic population. 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.

Video 1 Video 2 Video 3 Video 4

The terms insulindependent diabetes and non insulindependent diabetes characterize pathogenetic mechanisms of development DM and next therapy.

Pathogenetic and clinical difference of type 1 and type 2 DM. Signs 1. 2. 3. 4. 5. Age Beginning of disease Duration Ketosis, ketoacidosis Body weight DM type 1 Young (under 40) Acute Labile Often develops Decreased or normal DM type 2 Old, middle (over 40) Gradual Stable Rare develops Obesity in 80-90%of patients 6. Treatment Insulin, diet Diet, oral hypoglycemic agents or insulin 7. 8. Degrees of severity Season of disease beginning 9. Connection with HBAsystem 10. Level of insulin and Cpeptide Decreased or absent Frequently normal level Middle, hard Frequently autumn-winter period Present Absent Mild, middle, hard Absent

11. Antibodies to -cells

Present in 80-90% of patients on first week, month

Absent

12. Late complications 13. Mortality 14. Spreading

Microangiopathies Less than 10% 10-20%

Macroangiopathies More than 20% 80-90%

Etiologic classification of DM (1999). I. Type 1 of DM (destruction of -cells which mostly leads to absolute insulin insufficiency): - autoimmune; - idiopathic. II. Type 2 of DM (resistance to insulin and relative insulin insufficiency or defect of insulin secretion with or without resistance to insulin). III. Other specific types: - genetic defects of -cells function; - genetic defects of insulin action; - pancreatic diseases (chronic pancreatitis; trauma, pancreatectomy; tumor of pancreatic gland; fibrocalculosis; hemochromatosis); - endocrine disease; - drug exposures; - infections and others. IV. Gestation diabetes.

Stages of DM development 1. Prediabetes (risk factors or predispose factors): - obesity; - positive family history of DM; - persons which were born with weight more than 4,0 kg; - women in which: = were born children with weight more than 4,0 kg; =had abortions and dead child in anamnesis; - persons with: = atherosclerosis, hypertension; = autoimmune diseases; = furunculosis; = rubella, mumps, Coxsackie virus, infectious hepatitis, cytomegalovirus, infection mononucleosis. 1. Impaired glucose tolerance (latent DM). 2. Clinical manifestation of DM. Degrees of severity of DM. 1. Mild degree: 1) compensation can be achieved by diet; 2) fast serum glucose is less than 8.4 mmol/l; 3) glucosuria less than 20 gr./l (2 %); 4) proneness to ketosis does not occur; long-term (chronic) complications are rare or only functional stages can be observed. 2. Moderate degree: 1) compensation can be achieved by oral hypoglycemic agents (in patients with type II DM) or insulin (in patients with type 1 DM); 2) fast serum glucose is 8.4 to 14.0 mmol/l; 3) glucosuria is 20 to 40 gr./l (2 4 %);

4) ketosis can occur; long-term (chronic) complications can be observed (but not last stages). 3. Severe degree: 1) compensation can be achieved by insulin or oral hypoglycemic agents; 2) fast serum glucose is over 14,0 mmol/l; 3) glucosuria is over 40 gr./l (4 %); 4) ketosis is common and last stages of long-term (chronic) complications are present. Stages of compensations: 1. Compensation. 2. Subcompensation. 3. Decompensation. Criteria of compensative stage. 1. Patient hasnt new complains. 2. Fast serum glucose level is normal (but can be under 8.0 mmol/l in patients which havent 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. HbA1C < 7,0 % in patients with type 1 DM, < 6,5 % in patients with type 2 DM. 6. Comatose and precomatose status are absent. Criteria of subcompensative stage. 1. Patient may have new complains. 2. Fast serum glucose is high. 3. Glucosuria is present. 4. Glucose level fluctuation is over 4.4-5.5 mmol/l during the day. 5. HbA1C > 7,0 % in patients with type 1 DM, > 6,5 % in patients with type 2 DM. 6. Comatose or precomatose status are absent.

Criteria of decompensative stage: 1. Comatose or precomatose status are present. Duration of DM. 1. Stabile (glucose level fluctuation is under 4.4-5.5 mmol/l during the day and comatose or precomatose status are absent). 2. Labile (glucose level fluctuation is over 4.4-5.5 mmol/l during the day or comatose and precomatose status are present).

Pathophysiology of DM. Defective polymorphonuclear function infection Hyperglycemia glucosurea polyurea dehydration Insulin lack Hyperosmolality Proteolysis weight loss muscle wasting polyphagia Lipolysis free fatty acid release ketosis acidosis Clinical presentation. Signs and symptoms. The classic manifestation of type 1 DM include:

Video 1 Video 2
- polyurea (once plasma glucose concentration exceeds the renal threshold (about 180 ml/dl or 8 9 mmol/l) glucosurea ensues. Osmotic diuresis induced by glucose results in polyurea and subsequent polydipsia);

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- polidiosia

(as more water is excreted, the body requires more water intake);

- polyphagia - loss of weight

(this occurs to lack of energy); (energy (calories) is lost as glucose in the urine. Loss of water itself also contributes to weight loss. Increased proteolysis with mobilization of aminoacids leads to enhancement of protein catabolism and loss of weight, notably in muscle mass);

fatigue

and (probably occur as a result of decreased glucose utilization and electrolyte abnormalities); (develops due to increased lipolysis which cause the release of free fatty acids, which are metabolized to ketones by the liver).

weakness - acidosis

Presenting signs and symptoms of type 2 DM include: polyurea, polydipsia, polyphagia; the majority of individuals (80 85 %) are obese, but it can also occur in lean persons. Patients with DM are at risk if developing of chronic degenerative complications. Physical examination. Skin. The skin is a common target of DM. Many lesions can be observed, but none is specific to the disease, with the possible exception of necrobiosis lipoidica diabeticorum (it consists of skin necrosis with lipid infiltration and is also characteristically found in the pretibial area. The lesions resemble red plaques with distinct borders).

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The most common skin lesion is diabetic dermopathy (it is characterized by brown, atrophic, well-demarcated areas in the pretibial region which resemble sears), besides patients sometimes have xanthoma diabeticorum, which is usually located on the buttocks, elbows and knees, look like eruptions (but is not really diabeticorum since it occurs in the patients with lipoprotein abnormalities, particularly

hyperchylomicronemia, whether or not patient has DM)/ The skin is dry and itch. Infections of the skin by bacteria and fungi, candidiasis of the external female genitalia, hyperkeratosis, nail disorders are common in the patients with DM but nothing is specific with regard to their development. Subcutaneous adipose tissue. The abdomen type of obesity is common in patients with type 2 DM. Sometimes generalized subcutaneous adipose tissue atrophy can be observed in diabetics. Osteoporosis and osteoarthropaphy 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. 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

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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, sympatheticnervous-system dysfunction and volume expansion). Atherosclerosis of femoral, popliteal and calf larger arteries may lead to intermittent claudication, cold extremities, numbness, tingling and gangrene. Respiratory system. Mucomycosis of the nasopharinx, sinusitis, bronchitis, pneumonia, tuberculosis are more common in patients with diabetes than in nondiabetics. Kidneys and urinary tract. Renal disease include diabetic nephropathy, necrosing renal papillitis, acute tubular necrosis, lupus erythematosus, acute poststreptococcal and membranoproliferative glomerulonephritis, focal glomerulosclerosis, idiopathic membranous nephropathy, nonspecific immune complex glomerulonephritides, pyelitis, pyelonephritis, cystitis and others. Obviously, these abnormalities, with exception of diabetic nephropathy, are not at all peculiar to DM and can be observed in many other conditions. 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). The diagnosis of DM.

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The diagnosis of DM may be straightforward or very difficult. (The presence of the marked hyperglycemia, glucosuria, polyuria, polydipsia, polyphagia, lethargy, a tendency to acquire infections, and physical findings consistent with the disease should offer no difficulty in arriving at the correct diagnosis. On the other hand, mild glucose intolerance in the absence of symptoms or physical findings does not necessarily indicate that DM is present.) The diagnosis of DM include: 1. Clinical manifestations of DM. 2. Laboratory findings. 1) fasting serum glucose (if the value is over 6,1 mmol/l (120 mg/dl) on two or more separate days, the patient probably has DM); 2) the glucose tolerance test (GTT): If the diagnosis is still in doubt, then perform a GTT. 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: 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);

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- the criteria for diagnosing of impaired glucose tolerance are: a) a fasting serum glucose more than 5,5 mmol/l (100 gm/dl); b) a 2-hour postprandial serum glucose more than 7,8 mmol/l (140 gm/dl) but less than 11,1 mmol/l (200 gm/dl).

Glucose tolerance test (GTT)

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

Impaired fast 5,6 6,1 glucose tolerance

The major indication for an oral GTT is to exclude or diagnose DM (mostly type 2) in those suspected of having diabetes although fasting or symptomatic hyperglycemia is absent; e.g., in patients with a clinical condition that might be related to undiagnosed DM (e.g., polyneuropathy, retinopathy). Various conditions (other than DM) and drugs can cause abnormalities in the oral GTT. The criteria of DM do not apply to patients treated with drugs that can impair glucose tolerance (e.g., thiazids, glucocorticoids, indometacin, nicotinic acid, oral contraceptives containing synthetic estrogenes) or to patients who develop nausea, sweating, faintness or pallor during the test, or to have infections, hepatic, renal and endocrine disease that impairs glucose tolerance. 3) islet cell antibody levels will be positive prior to any insulin administration in 60 80 % of patients with type 1 DM; 4) C-peptide (it is not affected by antibodies to exogenous insulin and is used to distinguish type 1 and 2 DM if there is still a need after clinical determination); 5) glucose level in urine;

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6) glycohemoglobin (this test is an indicator of blood sugar control during the previous 2-to-3-month period); 7) acetonurea; 8) blood lipids and others. 3. Instrumental investigations usually are used to diagnose chronic complications of DM. 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

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blindness (e.g., macular edema or proliferative retinopathy with retinal detachment or hemorrhage. Evidence of retinopathy, rarely present at diagnosis in type 1 DM, is present in up to 20 % of type 2 DM patients at diagnosis. About 85 % of all diabetics eventually develop some degree of retinopathy. Diabetic retinopathy is classified according to the changes seen at background during ophthalmoscopic examination with pupils dilated. I. Background or nonproliferative 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).

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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.

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:

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- 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: - 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. II. Nonclinic stage. (Changes could be find only during instrumental examination.) Functional stage. (It is characterized by cold extremities, numbness, tingling, pain during physical examination.)

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III.

Organic stage. (It is characterized by trophyc changes: dry skin, hypo- or atrophy of muscles, ulcers, gangrene.)

Ischemic heart disease. 1. Cardiovascular changes tend to occur earlier in patients with DM when compared with individuals of the same age. 2. Frequency of myocardial infarction (MI) and mortality is higher in diabetics than that in nondiabetis of the same age. 3. The prognosis is even worse if ketoacidosis, or other complications of DM are present. 4. Diabetic patients have more complications of MI (arrhythmias, cardiogenic shock and others) than nondiabetic ones. 5. Often can observe atypical forms (without pain). 6. Male : female = 1 : 1 (nondiabetics = 10 : 1). Diabetic neuropathy. It is an old clinical observation that the symptoms of neuropathic dysfunction improve with better control of DM, lending support to the idea that hyperglycemia plays an important role. Accumulation of sorbitol and fructose in the diabetic nerves leads to damage of the Schwann cells and segmental demyelination.

Classification of diabetic neuropathy. I. Encephalopathy (central neuropathy) is characterized by decreased memory, headache, inadequate 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 response touch, burning of heels and soles. The skin becomes atrophic, dry and cold, hair loss may be

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prominent. The decreased response to touch and pain predisposes to burns and ulcers of the legs and toes.); truncal polyradiculoneuropathy (It is an asymmetric, and characterized by pain (which is worse at night), paresthesia and hyperesthesia; muscular weakness involves the muscles of the anterior thigh; reflexes are decreased; weight loss is common.); truncal monoradiculoneuropathy (It is usually involves thoracic nerves and the findings are limited to the sensory abnormalities in a radicular distribution.). III. Visceral dysfunction: 1) gastrointestinal tract: esophageal neuropathy (It is characterized by segmental distribution with low or absent resting pressure in the low or absent resting pressure in the lower esophageal sphincter and by absence of peristalsis in the body of the esophagus.); diabetic gastroparesis (It leads to the irregular food absorption and is characterized by nausea, vomiting, early satiety, bloating and abdomen pain.); involvement of the bowel (It is characterized by diarrhea (mostly at night time, postural diarrhea), constipation, malabsorption and fecal incontinence; 2) urinary tract: neurogenic vesicle dysfunction (It is characterized by insidious onset and progression of bladder paralysis with urinary retention.); 3) sexual disorders: retrograde ejaculation (which is caused by dysfunction of the pelvic autonomic nervous system); impotence, and sometimes decreased libido;

4) cardiovascular system:

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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). Neuropathic arthropathy (Charcots 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. Sign Temperature of the skin Color of the skin Pulsation vessels on Ischemic Decreased pallor or cyanotic peripheral decreased or absent Neuropatic normal normal or pink normal

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Edema Sensibility

Absent partly normal decreased

can be or decreased or absent

Ulcers Gangrene

peripheral (distant) Dry

under the pressure moist

References. 1. The Merck Manual of Diagnosis and Therapy (seventeenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. published by Merck Research Laboratories, 1999. P. 165 - 177. 2. Manual of Endocrinology and Metabolism (Second Edition)/ Norman Lavin. Little, Brown and Company.- Boston-New York-Toronto-London, 1994. - P. 519-527, 561574. 3. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 232-236.