MINISTRY OF HEALTH PROTECTION OF UKRAINE
Vynnitsa national medical university named after M.I.Pyrogov
«CONFIRM»
on methodical meeting of
endocrinology department
A chief of endocrinology
department, prof. Vlasenko M.V.
_________________
“_31_”_august___ 2012 y
METHODOLOGICAL RECOMMENDATIONS
FOR INDEPENDENT WORK OF STUDENTS
BY PREPARATION FOR PRACTICAL CLASSES
Scientific discipline
Мodule № 1
substantial module №1
Topic
Course
Faculty
Internal medicine
Basis of Internal medicine
“Diagnostic, treatment and prophylactic basis of
main endocrinology diseases”
Topic №2: Type I diabetes mellitus. Clinics. Diagnostics.
Features of the clinical course. Laboratory and instrumental
investigations in diagnostics of different types of diabetes
mellitus.
4
Medical № 1
Vynnitsa – 2012
METHODOLOGICAL RECOMMENDATIONS
for the students of 4-th course of medical faculty for preparation to the practical
classes from endocrinology
1.Тopic №2: Type I diabetes mellitus. Clinics. Diagnostics. Features of the clinical course.
Laboratory and instrumental investigations in diagnostics of different types of diabetes
mellitus.
2. Relevance of topic: Diabetes Mellitus is one of the major global health problems. It often
results in substantial morbidity and mortality primarily in the form of cardiovascular, eye and
kidney diseases, limb amputations. Diabetes Mellitus is the third leading cause of death in most
developed countries, there is also overwhelming evidence that it is epidemic in many developing
and newly industrialized nations. Diabetes Mellitus now is surely one of the most common and
challenging health problems. Prophylaxis, diagnosis and treatment approaches to diabetes are
priority problems in Ukraine.
3. Aim of lesson:
- to learn clinics of type I DM
- to learn diagnostic criteria of type I DM
- to learn laboratory and instrumental investigations in diagnostics of different types of DM
- to know the prevalence of Diabetes Mellitus and associated sign factors in the world.
- to understand the main etiological factors (genetic predisposition, role of human immunity, viral
infections, diet regimen, state of endocrine system, etc) in the development of Diabetes
Mellitus.
- to know about the correlation of different chains in the pathogenesis of this disease and the
research studies that support these correlations.
- to be able use in practice the new classifcation of Diabetes Mellitus (WHO, 1999).
- to be able interpret glycemic trials.
- to be able interpret the results of glycosylated hemoglobin and C-peptide assays.
4. References
4.1. Main literature
1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: Vinnytsya: Nova Knyha Publishers, 2008.-496 p.
2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G.
Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p.
3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p.
4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. –
608p.
5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H.
Wass. Oxford, University press,2006. – 1005p.
4.2. Additional literature
6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New
York: WC Graw-Hill Book, 1985. - P. 232-236.
7. Іnternatіonal Textbook of Dіabetes Mellіtus (Ed by R.A. Defronzo, E. Ferrannіnі, H. Keen,
P. Zіmmet. John Wіley & Sons, Ltd. England, 2004. – Vol. 1 – 1100p., Vol. 2 – 1913p.
8. Joslіn’s Dіabetes Mellіtus. Selected Chapters from the 14-th ed. Edіted by C. Ronald Kahn,
et al. Lіppіncott Wіllіams & Wіlkіns, USA, 2006. – 328p. Manual of Endocrinology and
Metabolism (Second Edition)/ Norman Lavin. – Little, Brown and Company.- Boston-New
York-Toronto-London, 1994. - P. 519-527, 561-574.
9. The diabetic foot. 2nd edition. Edited by A.Veves, J.M.Giurini, F.W. LoGerfo (ebs), Humana
Press, Totowa, New Jersey,2006. – 224p.
Basic Level.
Morphology of the pancreas and physiologic particularities of the pancreas endocrine function.
Regulation of glucose blood level.
Pathogenesis of metabolic changes in patients with insulin insufficiency.
Viruses with B-cell cytotropic action.
Students’ Independent Study Program.
You should prepare for the practical class using the existing text books and lectures. Special
attention should be paid to the following:
1. Epidemiological aspects of DM.
2. The main causes of increasing frequency of DM.
3. The role of virus infection in DM development.
4. The role of autoimmune process and other damage factors of the pancreas in DM development.
5. Pathogenesis of type I DM.
6. Differential diagnosis between type I and type II DM.
7. Classification of DM by WHO (1985, 1999).
8. Pathogenesis of tropical diabetes.
9. Pathogenesis and signs of gestation diabetes.
10. Laboratory diagnostic criteria of DM and impaired glucose tolerance.
11. Stages of severity of DM , diagnostic criteria of each stage.
12. Stages of DM compensation and diagnostic criteria of each stage.
13. Duration of DM.
Short content of the theme.
Classification of DM and impaired glucose tolerance by WHO (1985).
A. Clinical classes.
I. 1) Type I DM (insulindependent diabetes);
2) Type II DM (non insulindependent diabetes):
II.
-
in persons with obesity (80-90%);
-
in persons with normal weight.
DM which is secondary to some status and syndromes:
1) pancreatic diseases (chronic pancreatitis; tumor of pancreas);
2) endocrine diseases or hormonal abnormalities (pheochromocytoma, Cushing’s syndrome,
thyrotoxicosis and others);
3) drug exposures (glucocorticoids, thiazids, thyroid hormones, oral contraceptives);
4) a variety of a genetic syndromes;
5) insulin receptors’ abnormalities;
6) mixed status.
III.
Tropical diabetes:
1) pancreatic diabetes (it develops due to fibrocalculosis or protein-deficiency);
2) pancreogenic diabetes (it develops secondary to hemochromatosis).
IV.
Gestation diabetes.
V.
Impaired glucose tolerance :
-
in persons with obesity;
-
in persons with normal weight;
-
in persons with some syndromes and status.
B. Statistic risk factors (in patients with normal glucose tolerance but with high risk of DM
development):
-
previous impaired glucose tolerance;
-
potential impaired glucose tolerance.
The terms
“ insulindependent diabetes”
and “ non insulindependent diabetes “ characterize
pathogenetic mechanisms of development DM and next therapy.
Etiologic classification of DM (1999).
I.
Type 1 of DM (destruction of β-cells which mostly leads to absolute insulin insufficiency):
- autoimmune;
- idiopathic.
II.
Type 2 of DM (resistance to insulin and relative insulin insufficiency or defect of insulin
secretion with or without resistance to insulin).
III.
Other specific types:
- genetic defects of β-cells function;
- genetic defects of insulin action;
- pancreatic diseases (chronic pancreatitis; trauma, pancreatectomy; tumor of pancreatic
gland; fibrocalculosis; hemochromatosis);
- endocrine disease;
- drug exposures;
- infections and others.
IV.
Gestation diabetes.
(Gestation diabetes is defined as hyperglycemia diagnosed for the first time in pregnancy. It occurs
in individuals who have an inherited predisposition to develop diabetes and may take the form of
either type 1 or type 2 diabetes. Gestation diabetes is associated not only with increased rate of
perinatal morbidity and neonatal mortality but also with high incidence of subsequent diabetes in
mother. Treatment is with diet modification and insulin. Insulin does not cross placenta while oral
hypoglycemic agents cross placenta and therefore contrindicated.)
Stages of DM development
1. Prediabetes (risk factors or predispose factors):
-
obesity;
-
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.
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 I, 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.
Current formulation of the pathogenesis of type I 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 I diabetes individuals are HLA DR3, DR4 or DR3/DR4; on the
other hand, HLA DR2 confers protection against the development of type I 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
I diabetes.
Stages of type I DM development (by Flier, 1986).
I.
A genetic predisposition or changes of immunity.
II.
Putative environmental triggers.
III.
Active autoimmune insulities with β-cells destruction.
IV.
Progression of autoimmune insulities with destruction of >50 % of β-cells.
V.
Development of manifest DM.
VI.
Total β-cells destruction.
Pathogenetic and clinical difference of type I and type II DM.
Signs
IDD
NIDD
1.
2.
Age
Beginning of disease
Young (under 40)
Acute
Old, middle (over 40)
Gradual
3.
4.
Duration
Ketosis, ketoacidosis
Labile
Often develops
Stable
Rare develops
5.
Body weight
Decreased or normal
6.
Treatment
Insulin, diet
7.
8.
9.
Degrees of severity
Season of disease beginning
Connection with HBA-system
Middle, hard
Frequently autumn-winter period
Present
Obesity in 80-90%of
patients
Diet, oral hypoglycemic
agents or insulin
Mild, middle, hard
Absent
Absent
10.
Level of insulin and C-peptide
Decreased or absent
Frequently normal level
11.
Antibodies to β-cells
Absent
12.
Late complications
Present in 80-90% of patients on
first week, month
Microangiopathies
Macroangiopathies
13.
14.
Mortality
Spreading
Less than 10%
10-20%
Clinical presentation.
More than 20%
80-90%
Signs and symptoms.
The classic manifestation of type I DM include:
- 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);
- polidiosia
(as more water is excreted, the body requires more water intake);
- polyphagia
(this occurs to lack of energy);
- loss of weight
(energy (calories) is lost as glucose in the urine. Loss of water
itself also contributes to weight loss. Increased proteolysis with
mobilization of aminoacids leads to enhancement of protein
catabolism and loss of weight, notably in muscle mass);
- fatigue and weakness (probably occur as a result of decreased glucose utilization and
electrolyte abnormalities);
- acidosis
(develops due to increased lipolysis which cause the release of free
fatty acids, which are metabolized to ketones by the liver).
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).
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 II 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
deaths in diabetic patients, and mortality rate for the diabetics is higher than that for nondiabetics of
the same age who develop this complication.
Hypertension is common in patients with DM, particularly in the presence of renal disease (as
a result of atherosclerosis, destruction of juxtaglomerular cells, sympathetic-nervous-system
dysfunction and volume expansion).
Atherosclerosis of femoral, popliteal and calf larger arteries may lead to intermittent
claudication, cold extremities, numbness, tingling and gangrene.
Respiratory system.
Mucomycosis of the nasopharinx, sinusitis, bronchitis, pneumonia, tuberculosis are more
common in patients with diabetes than in nondiabetics.
Kidneys and urinary tract.
Renal disease include diabetic nephropathy (lesson 3), 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.
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 6,7 mmol/l (120 mg/dl) on two or more separate days,
the patient probably has DM);
2) the glucose tolerance test (GTT):
-
If the diagnosis is still in doubt, then perform a GTT.
Conditions for performing an oral GTT have been standardized:
no special dietary preparation is required for an oral GTT unless the patient has been ingesting
<150 gm/day of carbohydrate. Then give 150 – 200 gm carbohydrate daily for 3 days prior to
test;
-
unrestricted physical activity should proceed the test;
-
test is performed in the morning, following overnight fast of 10 to 16 hours;
-
subjects should remain seated, without prior coffee or smoking;
-
blood for glucose determination is obtained from an antercubital vein before glucose ingestion
and every 30 minutes far 2 hours after ingestion ;
-
the amount of glucose given is 75 g for adults (100 g pregnant women, and 1,75 g/kg of ideal
body weight for children). Patient have to drink glucose dissolved in 250 ml of water;
-
the criteria for diagnosing diabetes in pregnant adults are:
a) a fasting serum glucose more than 6,7 mmol/l (120 gm/dl);
b) a 2-hour postprandial serum glucose over 11,1 mmol/l (200 gm/dl);
-
the criteria for diagnosing of impaired glucose tolerance are:
a) a fasting serum glucose more than 5,5 mmol/l (100 gm/dl);
b) a 2-hour postprandial serum glucose more than 7,8 mmol/l (140 gm/dl) but less than
11,1 mmol/l (200 gm/dl).
The major indication for an oral GTT is to exclude or diagnose DM (mostly type II) 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 I DM;
4) C-peptide (it is not affected by antibodies to exogenous insulin and is used to distinguish type I
and II DM if there is still a need after clinical determination);
5) glucose level in urine;
6) glycohemoglobin (this test is an indicator of blood sugar control during the previous 2-to-3month period);
7) acetonurea;
8) blood lipids and others.
3. Instrumental investigations usually are used to diagnose chronic complications of DM.
Tests and Assignments for Self-assessment.
Multiple Choice.
Choose the correct answer/statement:
1. The patient of 22 years suffers from Diabetes Mellitus during 2 years. Diabetic complications are
not revealed. The patient is planning pregnancy The fasting level of glycemia is in limits 6.0-7
mmol/l. Choose the most informative method of diagnostic for the sanction of pregnancy which
provides avoidance of fetus pathology:
A. Glycated hemoglobin (HbAlc)
B. Glycemic profle
C. Glucosuric profle
D. С-peptide plasma level
E. Ketonuria
2. The patient of 33 years with the newly diagnosed diabetes with the help of the diet sustains the
glycemia after meal less than 10 mmol/l.
He abstains from the insulin therapy. For differentiated diagnostic of 1 and 2 types of diabetes it is
important to provide:
A. Defnition of islet cells antibodies pancreas
B. Oral glucose tolerance test
C. Defnition of the fasting level of glycemia
D. Defnition of glycated hemoglobin in blood
E. Defnition of fructosamine in blood
3. The man of 37 years complains of weight loss (5-6 kg for half-year), moderate dryness in the
mouth, thirst, polyuria. He feels ill for 7-8 months. Objective: temperature - 36,5 °С, pulse - 76
min., the blood pressure - 130/80 mmHg. The body height - 182 cm, weight - 87 kg. The skin and
mucosas are moderately dry. The fasting level of glycemia - 10-12 mmol/l; the glucosuria - 20 g/l,
reaction of urine to acetone - negative. What research will allow fnding out type of diabetes:
A. Defnition of the С-peptide level
B. Defnition of glucagon level
C. Defnition of НLA - antigens
D. Defnition of glycemic profle
E. Defnition of antibodies to the insulin
4. The patient of 39 years during 20 years suffers from bronchial asthma. Last 5 years he took
Prednisolonum because of serious attacks. In the hospital complained of polydipsia, dryness in the
mouth, the increased appetite and polyuria. Blood level glucose - 10,9 mmol/l. Your provisional
diagnosis:
A. Steroid diabetes
B. Diabetes Mellitus type 1
C. Diabetes Mellitus type 2
D. Renal diabetes
E. Diabetes connected to genetic defect of insulin
Answer: 1 – A. 2 – A. 3 – A. 4 – A.
Real-life situations to be solved:
1. Patient G., 62 years, (growth is 154 sm., weight is 68 kg) complains on itching of the skin and
genitalia, presence of the purulent wound of the left toe for a month. A fasting serum glucose is
10,6 mmol/l. What is your diagnosis?
Answer: Diabetes mellitus, type 2.
2. A 18-year-old female complains on polyuria, polydipsia, weight loss, and blurred vision. The
level of fasting serum glucose is 16 mmol/L. What is your diagnosis?
Answer: Diabetes mellitus, type 1.
Students Practical Activities.
Work 1 : Students’ group is divided into 2 sub-groups, that work near the patients’ bed: ask the
patients on organs and systems, take anamnesis of the disease , anamnesis of life, make objective
exam. With the teacher’s presence. In the class-room they discuss the patients, learn data of
laboratory and instrumental exam. of these patients.
1.To group the symptoms into the syndromes.
2.To find out the leading syndrome and make differential diagnosis.
3.To formulate the diagnosis.
4.To make a plan of treatment.
Methodological recommendation prepared assistant, c.m.s. Chernobrova O.I.
It is discussed and confirm on endocrinology department meeting
" 31 " august 2012 y. Protocol № 1.