Diabetes Mellitus

Part 1

Valentina Alexandrovna Divinskaya, assistant professor

Type I Diabetes Mellitus-
an autoimmune disease
with multifactorial (polygenic) type
of heredity

Development of type I DM depends on

genetic and exogenic factors
 GENETIC FACTORS
Diabetogenic Chromosome Diabetogenic Chromosome
loci location loci location

IDDM1 6р21(HLA genes) IDDM11 14q24 - q31

IDDM2 11р 15,5 IDDM12 2q 33
IDDM3 15q 26 IDDM13 2q 33
IDDM4 11q 13 IDDM15 6q 21
IDDM5 6q 25 IDDM17 21q 22,3
IDDM6 18 q IDDM18 5q 31 – q 33
IDDM7 2q 31 DXS1068 Хр11,4-р21,1
IDDM8 6q 25-q 27 GCK 7р
IDDM9 3q 21-q 25 NOS2 17q 11,2
IDDM10 10р11,2 CD4 12p12 – pter
 EXOGENIC FACTORS
β-cytotropic Enterovirus Coxsackie B
viruses Epidemic parotitis
(mumps), rubella,
chichenpox, measles,
adenovirus,
cytomegalovirus, etc.
Toxic Nitrosamines
Factors Nitrates, nitrites
Preparations β-adrenomimetics
α-interferon
corticosteroids
thyroid hormones
growth hormone
steroid contraceptives
nicotinic acid
cimetidine, indometacin
thiazides, vincristin
calcium channel inhibitors
Nutrition Excessive or imbalanced
factors nutrition:

- excess of animal proteins

- excess of purified carbohydrates

- taking cow’s milk in the first

months of child’s life
Psychoemotional or
physical stress:

- Secretion of contrainsular hormones

(adrenalin, cortisol, glucagon, etc) increases

Season (autumn-winter period):

- incidence of viral infections increases
 Endogenic Factors
Pancreas diseases:
 Pancreatitis (acute or chronic)
 Trauma, neoplasia
 Mucoviscidosis, hemochromatosis

Congenital defects of pancreas

development:
 Aplasia
 Hypoplasia
 Ectopia
Endocrine diseases:
 Thyrotoxicosis
 Acromegaly
 Cushing’s syndrome
 Aldosteroma
 Pheochromocytoma
 Glucagonoma
 Somatostatinoma
Pubertal period:

The increased production of

contrainsular hormones:

 somatotropin
 sex hormones
 STAGES OF AUTOAGGRESSION
DEVELOPMENT
I stage –
genetic predisposition:

 Symptoms of the disease are absent

 Genetic markers of type I DM:

Genes of HLA (Human Leukocyte Antigen)

system of II class,

HLA-DR and HLA-DQ (IDDM1):

- HLA-DR3, - HLA-DR4; - HLA-DR3/DR4

 II stage –
induction of autoimmune process

 Symptoms of the disease are absent

 Exogenic (endogenic) factors trigger

autoimmunity
 III stage -
autoimmune insulitis
 Symptoms of the disease are absent
 Autoantibodies appear:

- ICA – antibodies to β-cells

- IAA - antibodies to insulin
- GAD-65-antibodies to glutamate decarboxylase
- IA -2α – antibodies to tyrosine phosphatase-2
 IV stage –
latent form of type I DM
 Destruction of about 50% of β-cells
 Insulin secretion decreases:
(a low level of С-peptide)
 Impaired glucose tolerance
(at glucose tolerance test)
 Recurrent furunculosis
 Conjunctivitis, etc.
 V stage –
evident form of type I DM
(residual insulin secretion)
destruction of 80-90% of
β-cells
Manifestation of type I DM:
 Polyuria, polydipsia
 Hyperglycemia, glycosuria
 Ketonemia, ketonuria
 Metabolic acidosis, etc.
 VI stage –
evident form of type I DM
(absolute insulin insufficiency):
 Insulin secretion stops
(С-peptide is markly decreased or absent)
 Autoantibodies disappear
 Type I DM: a severe, lability course
 Development of late complications
of type I DM
Etiologic Classification of Glycemia Imbalance
(World Health Organization. Definition, Diagnosis
and Classification
Diabetes Mellitus and its Complications, 1999)

1. Type I DM:
(destruction of pancreas β-cells and
absolute insulin insufficiency)

 А. Autoimmune
 Б. Idiopathic
2. Type II DM

3. Other specific types of

diabetes

4. Gestational diabetes mellitus

 Сlinical signs of type I DM
 Polydipsia (3 -10 L a day are drunk)
 Polyuria
 Weakness, malaise
 Headache, sleepiness

 Appetite:
- at onset of disease – increased
- at progressing ketoacidosis – decreased
- at the peak of disease - anorexia
 Nausea, coffee-ground vomit
 Pains in the abdomen:
- at first: spastic intermittent pains
round the umbilicus or in the right hypochondrium
- later: intensive and constant pain
- sometimes symptoms of pseudoperitonitis are
present: (abdominal muscle defence and
Blumberg's sign)
 Stool:
- In children before 3 years – diarrhea
- In children over 3 years - constipations
Dehydration (loss of weight):
 SKIN:
- dry, desquamation, acrocyanosis
(sometimes mycotic and purulent infection)

 Hyperemia of cheek - (rubeosa diabetica)

 Mucous membranes:
- dry, hyperemic
- fissures at the angles of mouth
- crack lips

 Tongue: scarlet, dry, white-coated

(later brown-coated)
 Girls may have vulvovaginitis
Boys may have – balanoposthitis
Subcutaneous fatty layer:
considerably thinned or disappears

Tissue turgor: sharply decreased

Toxic Kussmaul's respiration

Acetone smell from the mouth
 Hepatomegaly

 Heart sounds:
muffled, tachycardia
 Pulse: frequent, weak

 ABP: hypotonia, collapse

 Leukocytosis

 Metabolic acidosis
 Diagnostic Criteria
of Diabetes Mellitus
(WHO, 1999)

Normal glycemia level :

Fasting: < 5.6 mmol/l

In 2 hours after glucose load:

< 7.8 mmol/l

 Diabetes Mellitus

Fasting glucose level:

≥ 6.1 mmol/l

In 2 hours after taking food:

≥ 11.1 mmol/l
 Disturbance of Tolerance
to Glucose

Fasting glucose level: < 6.1 mmol/l

In 2 hours after glucose load:

≥ 7.8 - < 11.1 mmol/l
Impaired Fasting Glycemia Level

Fasting glucose level:

≥ 5.6 - < 6.1 mmol/l

In 2 hours after glucose load:

< 7.8 mmol/l
 Treatment of Type I Diabetes
Mellitus

Basic principles of treatment of type I DM

Insulinotherapy Diet Physical

exertion

Self-control of glycemia
Basic Principles of Diet
1. Estimation of carbohydrates is made
in grains (gr).

2. Frequent diet regime (6 times a day).

3. To exclude purified carbohydrates.

4. To provide high content of cellulose.

Daily calorie content of nutrition = 1000 + (100 × N)
(N – age in years)

Proteins Fats Carbohydrates

15 - 20 % 25 - 30 % 50 - 60 %
 Distribution
of daily calorie content of nutrition
Breakfast – 25%
Breakfast-2 - 10-15%
Lunch– 25-30 %
Tea time – 5-10 %
Dinner– 20-25 %
Supper – 5-10 %
 Grains
1 gr = 10 - 12 g carbohydrates
1 gr = 40 - 45 kcal
1 gr = 20 g white bread

1 gr increases glycemia
by 1.7 – 2.8 mmol/l

1-2 U of insulin are necessary per 1 gr

 Daily amount of grains for
children of different age (2003)

Age Daily amount of grains

1-3 years 10 - 11

4-6 years 12 - 13

7-10 years 15 - 16

11-14 years Girls Boys

16 - 17 18 - 20
15-18 years Girls Boys
18 - 20 19 - 21
 INSULINOTHERAPY
basic-bolus regime

Physiology:
 Basal (constant) secretion of insulin –
for basal metabolism

 Bolus (peak) secretion of insulin –

in response to food intake
 Intensified scheme
Basal level is provided by intermediate-acting
(or long-acting) insulin in a dose of:

50 % of daily dose

Injections: 1-2 times a day – in the morning and

evening, only in the morning (or only in the evening)

Bolus level is provided by short-acting

(ultrashort-acting) insulin in a dose of:

50 % of daily dose

Injections : before breakfast, lunch, dinner

 Classification of Insulins
Ultrashort-acting Insulins
Type of insulin Onset of Peak Duration of
action action action
Apidra 5 -15 min 1-2 h 3-4h
(insulin glulisin)

NovoRapid 10 -20 1-3 h 3-5h

(insulin aspart) min

Humalog 0 - 15 min 1 h 3.5 - 4 h

(insulin lizpro)
 Classification of Insulins
Short-acting Insulins
Type of insulin Onset of Peak Duration of
action action action

Actrapid 0.5 -1 h 1-3h 6-8h

Humulin R 0.5 - 1 h 1-3h 6-8h

 Classification of Insulins
Intermediate-acting insulins
Type of insulin Onset of Peak Duration of
action action action

Protafan NM 1-2h 4 - 12 h Up to 24 h

Humulin 1-2h 4 - 12 h 17 - 22 h
NPH
 Classification of Insulins
Long-acting Insulins
Type of insulin Onset of Peak Duration of
action action action

Lantus 1-2 h absent 24 h

(insulin
glargin)

Levemir 1-2 h absent 24 h

(insulin
detemir)
 Combined Insulins

 Nоvоmix 30 (Novo Nordisk):

(NоvоRаpid 30% + Protamin NоvоRаpid 70%)

 Humulin 3 (Eli Lilly):

(Short-acting Insulin 30% + Insulin -isofan
70%)

 lizpro Мix 25 (Eli Lilly):

(Humalog 25% + Protamin Humalog 75%)
 Insulinotherapy
An average daily dose of insulin
I type DM – first year 0.5 - 0.6 U/kg/day

«honey moon» 0.1 - 0.2 U/kg/day

(period of remission)
I type DM – second year 0.7 - 0.8 U/kg/day
(after remission)
Prepubertal period 0.6 - 1.0 U/kg/day

Pubertal period 1.0 - 2.0 U/kg/day

Decompensation state 1.0 - 1.5 U/kg/day

 basic-bolus regime
Before Before lunch Before dinner At bedtime
breakfast (21-22 h)
Actrapid Actrapid Actrapid Protafan
+
Protafan
Apidra Apidra Apidra Lantus

NovoRapid NovoRapid NovoRapid Levemir

Nоvоmix NovoRapid Nоvоmix

 Physical Exertion
1. Increases sensitivity of tissues to insulin and
allows to decrease an insulin dose

2. Increases rate of glucose absorption

by muscles

3. Increases rate of insulin absorption

from the injection site

4. Normalizes catecholamine secretion

 Physical Exertion
(basic rules)

1. Physical exertion should be dosed, regular

2. Before physical exertion blood glucose

should be within the limits of 6-13 mmol/l

3. Glycemia over 13 mmol/l –

risk of ketoacidosis
4. Glycemia below 6 mmol/l –
risk of hypoglycemia
 Criteria of glycemic control of type I DM
(ISPAD CONSENSUS GUIDELINES, 2000)

Criteria Healthy Type I DM Type I DM Type I DM

compensa- subcompen- decompen-
tion sation sation
Fasting 3.6 – 6.1 4.0 -7.0 7.0 – 9.0 > 9.0
glycemia

Glycemia 4.4 – 7.0 5.0 – 11.0 11.1 – 14.0 > 14.0

in 2 hours

Glycemia 3.6 – 6.0 not < 3.6 < 3.6 < 3.0
at night Not > 9.0 or > 9.0 or > 11.0
HbA1c % < 6.0 < 7.6 7.6 – 9.0 > 9.0
GLUCOMETERS
Late Complications of Type I DM
Diabetic neuropathy
Diabetic nephropathy
Diabetic retinopathy
Diabetic cataract
Diabetic hieropathy
Fatty hepatosis
Lipoid necrobiosis
Diabetic encephalopathy
Diabetic myocardiodystrophy
Physical and sexual retardation
Mauriac's syndrome
Nobekur’s syndrome
Lipodystrophies (insulinotherapy complications)
 Diabetic Neuropathy
Polyneuropathy:
 Decrease of tactile, temperature, pain, vibration
sensitivity in low extremities
 Dull pains in extremities
 Paresthesias, spasms
 Decrease of knee reflexes
 Absence of Achilles reflexes
 Dry skin, hyperkeratosis
 Disturbance of nail growth
 Infectious complications
Autonomic (vegetative) neuropathy:

Cardiovascular system -
(arrhythmias, palpitation, change of arterial blood
pressure, dizziness, myocardial ischemia)

Gastrointestinal tract -
(nausea, vomiting,diarrhea or constipations)

Genitourinary tract –
(hypotonia and dilatation of the urinary bladder)
 Diabetic Nephropathy
is glomerulosclerosis and chronic renal insufficiency

Stages of diabetic nephropathy

(C.E. Mogenser, 1983)

I stage – kidney hyperfunctions:

 Hyperfiltration (GFR >140 ml/min)

 Kidney hypertrophy
 Protein level in urine is normal
(< 30 mg/day)
II stage –
structural changes in kidneys:

 Thickening of basal membrane

 Hyperfiltration - GFR >140 ml/min.

 Protein in urine is normal: < 30 mg/day

III stage –
onset of diabetic nephropathy:

 GFR (glomerular filtration rate) -

normal

 Microalbuminuria - 30 - 300 mg/day

 Arterial hypertension (periodic)

IV stage –
marked diabetic nephropathy:

 GFR – moderately decreased

 Proteinuria: > 500 mg/day

 Arterial hypertension (constant)

 Glomerulosclerosis - 50-75 %
V stage – uremia:

 GFR – sharply decreased:

<10 ml/min.
 Proteinuria: > 500 mg/day
 Arterial hypertension (constant)
 Total glomerulosclerosis
 Uremic intoxication
Diabetic Retinopathy
(lesion of the retina)

Stages of Diabetic Retinopathy

(E.M. Kohner M. Porta, 1992)
I stage – non-proliferative:
 Microaneurysms
 Retina hemorrhage
 Reduction of visual acuity (insignificant)
I stage– non-proliferative
 Stages of Diabetic Retinopathy
(E.M. Kohner M. Porta, 1992)

II stage – preproliferative:

Multiple hemorrhage
Dilatation of capillaries
Local thrombosis
Formation of shunts (new vessels)
Reduction of visual acuity (significant)
II stage – preproliferative:
 Stages of Diabetic Retinopathy
(E.M. Kohner M. Porta, 1992)

III stage– proliferative:

 Retinal detachment
 Vitreous body hemorrhage
 Loss of vision (blindness)
III stage– proliferative
Лазерная фотокоагуляция
Diabetic Cataract –
opacity of the ocular lens

Due to long hyperglycemia

and formation of sorbitol in the cells
 Diabetic Hieropathy
- affection of interphalangeal joints of hands

1 stage – affection of up to
3 fingers

2 stage – affection of 3 and

more fingers

3 stage – fibrosis of palmar

aponeurosis
Lipoid
Necrobiosis -
skin lesions
due to increased
glucose content
in the skin,
microangiopathy
and lipoid collagen
dystrophy
 Diabetic Encephalopathy
 Attacks of headaches
 Sensation of pressure in the eyeballs
 Dizziness
 Malaise, fatigue, sleepiness
 Emotional lability
 Decrease of capacity for work
 Nystagmus
 Muscle hypotonia
 Decrease of abdominal reflexes
 Diabetic Myocardiodystrophy
1). Disturbance of glucose utilization by myocardium
2). Increased consumption of lipids and proteins by
myocardium

Dyspnea on physical exertion

palpitation
Heart pain
dilatation of heart borders
tachycardia
weakening of heart tones
systolic murmur at the apex and
in Botkin-Erb’s point
Fatty Hepatosis
(fatty infiltration of the liver)

1. Exhaustion of glycogen depot in the

liver
2. Accumulation of free fatty acids and
neutral lipids in hepatocytes

Liver:
Enlarged, dense, painless
Mauriac's
Syndrome –
results from
prolonged
decompensation
of type I DM
(insufficient dose
of insulin
and / or
nonfollowing
a diet)
Mauriac's Syndrome

Retardation of growth
Obesity (Cushing's syndrome)
Hyperemia of face
Xanthochromia of palms and soles
Delay of sexual development
Hepatomegaly
Osteoporosis
Frequent ketoacidosis and
hypoglycemia states
Nobekur's Syndrome

- results from prolonged

decompensation of type I DM

 Retardation of growth
 Delay of sexual development
 Hepatomegaly

 Obesity is absent!