Transcript Diabetes Mellitus in Children

Diabetes Mellitus in
Children
DM Type I
Olena Riga
KhNMU
Diabetes Mellitus
DM is a syndrome of disturbed
energy metabolism caused by
deficiency of Ins secretion or Ins
action at the cellular level that
results in altered fuel homeostasis
affecting carbohydrate, protein,
and fat.
World Statistics
246.000.000 patients with DM in the
World were reiterated at 2006 yr
380.000.000 – prognosis for 2025 yr
Every 10 seconds one patient
die from DM
World Statistics
Every years the DM type I
occurs in 70 000 children
EURODIAB: every year
increasing DM type I in adults
in 3% and in 4.8% in children
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
(на 1000 населения)
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
Mortality DM type I (1922-1972)
Mortality from DM type I
from 90% to 50%
Снизиласьon
на the
40% 40%
Decrease
С
1922 г.
1
9
2
2
г
.
н
и
з
и
л
а
с
ь
н
а
4
0
%
1972 г.
1
9
7
2
г
.
Green
Green A.
A. //// Diabetologia.
Diabetologia. –– 1985.,
1985., 28:
28: 33
3
Historical Data
Increasing of the urination was described
1500 yrs B.C. at Egypt
 Fist clinical description of the DM by Cels
(30-50 yrs Anno Domini)
 The term “Diabayo” – passing through
(30-90 yrs Anno Domini)
 1600 yr – the term “mellitus” (lat)- honey
due to sweet urine taste

Historical Data (c’d)
1674 yr Tomas Willis (Oxford) supposed
that the sugar pass to urine from blood
 1841-1848 yrs Trommer and Felling –
methodic of the definition of blood sugar
by Copper Oxide
 1796 Rallo at first proposed to restrict the
carbohydrate intake to patients with DM

Historical Data (c’d)
1813-1878 yrs Klod Bernar
discribed the pathogenesis of
hyperglycemia
 1869 yr medical student Paul
Langerhans discovered the
cells congestion in pancreas
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1874 yr Kussmaul discovered
ketons, aceton, described specific
type of breathing
Historical Data (c’d)
1989 yr Mering & Minkovsky established
that the dogs with pancrectomy develops
hyperglycemia and further death
 1902 yr Opy – described the degeneration
of the Langergans islet
 1907 yr Lane Bersley (Chicago) discovered
pancreatic cells type A and type B

Historical Data (c’d)
 1955
yr Sanger
(Cambridge) –
discovery
aminoacid
structure in
molecular of Ins
С-peptide is the predecessor of Ins
1969 yr Steiner – invented biosynthesis of
the C-peptide
1973 yr mono component - Ins was
synthesized
Etiologic classification of DM
I. Type I DM (β-cell
destruction,
absolute Ins
usually leading to
deficiency)
II. Type II DM (may rang from
predominantly Ins resistance with
relative
Ins
deficiency
to
a
predominantly receptor defect with
Ins resistance)
Etiologic classification of DM (c’d)
III. Other specific types
A.
B.
C.
D.
E.
Monogenic DM
Exocrine pathology of pancreas
Endocrine diseases
Drugs
Genetics syndromes such as Down,
Turner etc.
The onset DM
type I occurs
predominantly
in childhood,
with median age
of 7 to 15 yrs,
but it may
present at any
age
DM type I
 DM
type I is
characterized
by autoimmune
destruction of
pancreatic βcells
DM type I
Β-cells
destruction
may be due to
drugs, viruses,
mitochondrial
defects,
ionizing
radiation, etc
DM (DM I type)
Genetic susceptibility to type I DM is
controlled by alleles of the major
hystocompatability complex class II
genes expressing human leukocyte
antigens (HLA) that associated with
antibodies to glutamatic acid
decarboxylase
DM I type is associated with other
autoimmune diseases such as
thyroiditis, Celiac disease, multiply
sclerosis, Addison disease, and etc.
Manifestation of the DM if the 8090% betta cells were destructed
DM II type –resistant to Ins
Etiologic classification of DM (c’d)
III. Other specific types
defects of β-cell function
chromosome 12, HNF-1ά - MODY-3
chromosome 7, glucokinase, MODY-2
chromosome 20, HNF-4ά - MODY-1
Mitochondrial DNA
MODY- maturity-onset diabetes of the
young *HNF –hepatocyte nuclear
factor gene mutation
 Genetic
Etiologic classification of DM (c’d)
III. Other specific types
 Genetic
defects in
Ins action
Type A Ins resistance
Leprechaunism
Rabson-Mendenhall
syndrome
Lipoatropic diabetes
(Lorens syndrome)
Type A
Adolescence
 Ins-resistance in absence of obesity
 Acanthosis Nigricans
 Androgen Excess & Hypertrichosis
 Gene involved Insulin receptor
 Recessive

Leprechaunism
Congenital
 Abnormal faces
 Large genitalia
 SGA and growth retardation
 Rarely survive infancy
 Acanthosis Nigricans
 Gene involved Insulin receptor & GHresistence
 Recessive

Leprechaunism
Rabson-Mendenhall
Congenital
 Extreme Growth retardation
 Abnormal dentition
 Acanthosis Nigricans
 Androgen Excess & Hypertrichosis
 Gene involved Insulin receptor
 Recessive

Lipodystrophy
Lorens syndrome
Congenital or Adolescence
 Loss of subcutaneous fat – partial or total
 Acanthosis Nigricans
 Androgen Excess & Hypertrichosis
 Gene involved Total: Seipin & AGPAT2
(recessive) Partial :Lamin AC & PPARG
(dominant)

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The key feature of all insulin resistance
syndromes are acanthosis nigricans,
androgen excess and massively raised
insulin concentrations in the absence of
obesity
Maternal transmission of mutated or deleted
mitochondrial DNA (mtDNA) and the
mitochondrial tRNA (leu(UUR)) gene (B) can
result in maternally inherited diabetes.
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MELAS syndrome:
mitochondrial myopathy
Encephalopathy
lactic acidosis
stroke-like syndrome
Mitochondrial diabetes is commonly associated
with sensorineural deafness and short stature.
The diabetes is characterised by progressive
non-autoimmune beta-cell failure and may
progress to needing insulin treatment rapidly.
Etiologic classification of DM (c’d)
III. Other specific types
Diseases of the exocrine pancreas
Pancreatitis
Trauma, pancreatomy
Neoplasia
Cystic fibrosis
Hemochromatosis
Fibrocalculous pancreatopathy
Pancreatic resection

Etiologic classification of DM (c’d)
III. Other specific types

Endocrinopathies
Acromegaly
Cushing disease
Glucagonoma
Pheochromocytoma
Hyperthyroidism
Somatostatinoma
Aldosteronoma
Etiologic classification of DM (c’d)
III. Other specific types
 Infections
Congenital rubella
Cytomegalovirus
Hemolitic-uremic
syndrome
→→→
Etiologic classification of DM (c’d)
III. Other specific types
Genetic syndromes
Down syndrome
Klinefelter syndrome
Wolfram syndrome
Friedreich ataxia
Huntington chorea
Laurence-Moon &
Bardet-Biedl syndrome
Myotonic distrophy
Porphyria
Prader-Willi syndrome

Wolfram syndrome (DIDMOAD)
DI-diabetes insipidus
DM-diabetes mellitus
OA-optical atrophy
D- deafness
????
Prader-Willi syndrome
Etiologic classification of DM (c’d)
III. Other specific types
Gestational DM
 Neonatal DM

Neonatal diabetes
There is good evidence that diabetes
diagnosed in the first 6 months is not
Type I DM as neither autoantibodies nor
an excess of high Type I HLA susceptibility
are found in these patients.
 Neonatal diabetes is insulin requiring
diabetes which is usually diagnosed in the
first three months of life.

Neonatal diabetes
Clinically two
subgroups were
recognized: transient
neonatal diabetes
mellitus (TNDM) &
permanent neonatal
diabetes mellitus
(PNDM)
Transient neonatal diabetes
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anomalies on 6q24 locus
DM associated within the first week and resolves
around 12 weeks
50% of cases DM will reoccur during the
paediatric age range
Macroglossia seen in 23%
Initial glucose values can be very high (range1257 mmol/L) and so insulin is used initially
although the dose can rapidly be reduced.
The response to oral treatment such as
sulphonylureas or metformin is uncertain
Permanent neonatal diabetes
Kir6.2 mutations
Only 10% have a remitting form of DM that may
latter relapse
 Most patients have isolated DM
 20% have developmental delay of motor and
social function & generalized epilepsy so called
DEND syndrome Developmental delay, Epilepsy
and Neonatal Diabetes
 Patients have all the clinical features of insulin
dependency do not have detectable C peptide.
It has been shown that these patients can not
be successfully treated with oral sulphonylureas.
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
Etiologic classification of DM (c’d)
III. Other specific types
Drug- or chemical-induced
Pentamidine, Nicotinic acid
Glucocorticoids
Thyroid hormone
ß-adrenergic agonists
Thiasides
Β-Interferon & others

Insulin

Ins is synthesized on the ribosoms of
pancreatic islet beta cells and is released
into the circulation as a molecule
comprised of two separate straight
polypeptide chains linked by disulfide
bridges between and within these chains
Ins is the major anabolic hormone
of the body
Ins action is on
target cells in
tissues such as
liver,
adipocytes and
muscle
Metabolic events during the fed
and fasted states (liver)
High-Ins (fed) & Low Ins (fasted)state
Glucose uptake
Glucose production
Glycogen synthesis
Glycogenolysis
Absent gluconeogenesis Present G-sis
Lipogenesis
Absent l-sis
Absent ketogenesis
Ketogenesis
Metabolic events during the fed
and fasted states (muscle)
High-Ins (fed) & Low Ins (fasted)state
Glucose uptake
Absent glucose uptake
Glucose oxidation Fatty acid άketooxydation
Glycogen synthesis Glycogenolysis
Protein syntesis
Proteolysis and amino
acid release
Metabolic events during the fed
and fasted states (Adipose tissue)
High-Ins (fed) & Low Ins (fasted)state
Glucose uptake
Absent Glucose uptake
Lipid synthesis
Lipolysis and fatty acid
release
Triglyceride uptake Absent triglyceride
uptake
Pathophysiology of DM type I

Progressive destruction of β-cells leads to
progressively more severe Ins deficiency
with involving classical stress hormones
(epinephrine, cortisol, growth hormone,
and glucagon) so called counterregulatory hormones
Ins
deficiency, acting in concert
with the excessive concentration
of epinephrine, cortisol, growth
hormone, and glucagon will result
in unrestrained glucose
production while glucose
utilization is impaired, so that
hyperglycemia develops.
Ins
deficiency and elevating
counter-regulatory hormones
leads to lipolysis and impaired
lipid synthesis and elevation in
plasma total lipids, cholesterol,
triglycerids, and free fatty acids.
 The
hormonal interplay of Ins
deficiency and glucagon excess
shunts the free fatty acids to
ketone body formation
Acetone
Acetoacetate
Β-oxyoil acid
Accumulation of ketoacids results in
metabolic acidosis and the compensatory
rapid deep breathing, which is an attempt
to excrete excess CO2 (Kussmaul’s
respiration)
 Acetone, formed by nonenzymatic
conversation of acetoacetate, is
responsible for the characteristic fruity
odor of the breath

Ketones are readily excreted in the urine
in association with cations, further
compounding losses of water and
electrolytes (dehydration)
 With progressive dehydration, acidosis,
hyperosmolality, and diminished cerebral
oxygen utilization, consciousness becomes
imparired and ultimately results in coma.

DM
The loss of weight is on the basis of the
catabolic state and urinary losses of
calories due to polyuria
 The no effective calories balance lead to
the hunger & polyphagia (despite the
increase food intake calories cannot be
utilized) & weight loss occurs

DM

Glucosuria results when the renal
threshold of ≈ 160 ml/dl (> 8.88 mmol/L)
is exceeded; the resultant osmotic diuresis
produces polyuria, dehydration, an
increase in osmolality, and compensatory
polydipsia
DM

Pyogenic skin infection are most
uncommon as a presenting complaint,
although vaginitis in teenage girls may be
the presenting feature
Clinical presentation
About 30% of patients initially present with
frank diabetic ketoacidosis:
Air hunger
Kussmaul’s respiration
Acetone on the breath
Obtundation of consciousness or coma
Vomiting
Dehydration
Hyperglycemia
Hyperglycemia
Clinical presentation
Polyuria
 Polydipsia
 Polyphagia
 Weight loss
 Lethargy
 weakness
These symptoms may be present for days to
weeks

Particularities DM in infants
Lability of the water &
mineral metabolism
 Stopping or loss body
weight
 Appetite increase or
normal
 Thirst, active sucking

Particularities DM in infants

Starch napkins or
sticky stains due to
glucosuria

Dry skin, ↓ turgor,
skin infection
2 types of DM manifestation in
infants
First – acute onset, severe dehydration,
intoxication, vomiting, coma as a toxicoinfection shock
 Second – dystrophy develops gradually,
infection diseases connect
 Ketonuria is absent to 4 mo old due to
liver immaturity

Diagnosis of DM N.B!

Clinical presentation & paraclinic: hyperglicemia,
glucosuria, ketonuria
Additional:
 ↓ or absents of C-peptide
 ↑ glicolized Hb (HbAic)
 ↑ fructosamine
 presents of the antibodies to ß cells, Ins
and to differens glutamatdecarboxilase
isoformes
Criteria of DM compensation
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The aim of treatment –”QULITY OF
LIFE”
The adequate growth & development
of child
Active social position in life & society
Decreasing acute complication and
prolong late complications of DM
Normal life duration
Criteria of DM compensation (c’d)
in childhood
Glucose level fasting 4-8 mmol/L
 Glucose after feeding 10-11mmol/L (3.38.3 mmol/L – less than renal threshold)
 Night Glucose level 6-8 mmol/L
 Episodes of Hypoglycemia are absent
 Glucose absent in urine

Criteria of DM compensation (c’d)
Normal lipid, protein and mineral
metabolism
 HbAic, % - 5-7
 Cholesterol mmol/L -< 5.2
 Triglicerids mmol/L - < 1.7

Differential Diagnosis
Diabetes Insipidus
 Appendicitis
 Fancony syndrome
 Diabetes Mellitus type II

Factors influencing
vasopressing secretion
INCREASED SECRETION
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Hypovolemia
Hyperosmolality
Upright position
Central hyperthermia
Stress and anxiety
Cerebral disease
Chest disease
Malignancies
Drugs (Carbamazepine, clofibrate Nicotine, angiotensin
II Cholinergic drugs, Morphine, barbiturates)
Factors influencing
vasopressing secretion
DECREASED SECRETION
Hypervolemia
 Hyperosmolality
 Recumbent position
 Central hyperthermia
 Diabetes insipidus
 Drugs & Alcohol (Dilantin, Anticholinergic
agents)

POLYURIC CONDITIONS
MIMICKING VASOPRESSIN
DEFICIENCY

Physiologic suppression of vasopressin
secretion
Psychogenic polydipsia
 Organic polydipsia (hypothalamic disease)
 Drug induced polydipsia (thioridazine,
tricyclics)

POLYURIC CONDITIONS
MIMICKING VASOPRESSIN
DEFICIENCY

Reduced renal responsiveness to vasopressin
Genetic: nephrogenic diabetes insipidus medullary cystic
disease
 Pharmacologic: lithium, demeclocycline, penthrane,
diuretics
 Osmotic diuresis: diabetes mellitus reduced nephron
population
 Electrolyte disturbance: hypercalcemia hypokalemia
 Renal disease:postobstructive diuresis, renal tubular
acidosis pyelonephritis, papillary necrosis, sickle cell
disease
 Hemodynamic: hyperthyroidism

Diabetic ketoacidosis
Hyperglycemia
 Ketonemia
 Acidosis (pH≤7.3 & bicarbonate less than
15 mEq/L)
 Glucosuria
 Ketonuria

Complications of DM (acute)
Ketoacidosis, ketoacidotic coma
 Dehydration
 Nonketotic hyperosmolar coma
 Hypoglicemia, hypoglicemic coma
 Lactoacidotic coma

Complications of DM
Somogy phenomenon
 Dawn phenomenon
 Brittle Diabetes

Complications of DM (long-term)
Diabetic retinopathy
 Diabetic nephropathy
 Angiophathy of lower
extremities
 Diabetic neuropathy
(periferal, central,
autonomic)

Complications of DM (long-term)
Mauriac syndrome, Nobecur syndrome
 Syndrome of limited joint mobility
(hairopathy)
 Skin pathology (lipoid necrobiosis,
lipodystrophy, paronichia and etc)

lipoid necrosis's
lipoid necrobiosis
lipoid necrobiosis
Diabetes Mellitus in Children