2. Diabetes Mellitus in Children
DM Type I
Olena Riga
KhNMU

3. 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.

4. Every 10 seconds one patient die from DM
World Statistics
patients with DM in the World were reiterated at 2006 yr
– prognosis for 2025 yr
Every 10 seconds one patient die from DM

5. World Statistics
Every years the DM type I occurs in children
EURODIAB: every year increasing DM type I in adults in 3% and in 4.8% in children

7. Mortality from DM type I
Decrease on the 40%

8. 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

9. Historical Data (c’d)
1674 yr Tomas Willis (Oxford) supposed that the sugar pass to urine from blood
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

10. Historical Data (c’d)
yrs Klod Bernar discribed the pathogenesis of hyperglycemia
1869 yr medical student Paul Langerhans discovered the cells congestion in pancreas
1874 yr Kussmaul discovered ketons, aceton, described specific type of breathing

11. 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

12. Historical Data (c’d)
1955 yr Sanger (Cambridge) –discovery aminoacid structure in molecular of Ins

13. С-peptide is the predecessor of Ins 1969 yr Steiner – invented biosynthesis of the C-peptide

14. 1973 yr mono component - Ins was synthesized

15. Etiologic classification of DM
I. Type I DM (β-cell destruction, usually leading to absolute Ins deficiency)
II. Type II DM (may rang from predominantly Ins resistance with relative Ins deficiency to a predominantly receptor defect with Ins resistance)

16. Etiologic classification of DM (c’d) III. Other specific types
Monogenic DM
Exocrine pathology of pancreas
Endocrine diseases
Drugs
Genetics syndromes such as Down, Turner etc.

17. The onset DM type I occurs predominantly in childhood, with median age of 7 to 15 yrs, but it may present at any age

18. DM type I
DM type I is characterized by autoimmune destruction of pancreatic β-cells

19. DM type I
Β-cells destruction may be due to drugs, viruses, mitochondrial defects, ionizing radiation, etc

20. 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.

22. Manifestation of the DM if the 80-90% betta cells were destructed

23. DM II type –resistant to Ins

24. Etiologic classification of DM (c’d) III. Other specific types
Genetic 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

25. 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)

26. Type A Adolescence Ins-resistance in absence of obesity
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive

27. Leprechaunism Congenital Abnormal faces Large genitalia
SGA and growth retardation
Rarely survive infancy
Acanthosis Nigricans
Gene involved Insulin receptor & GH-resistence
Recessive

28. Leprechaunism

29. Rabson-Mendenhall Congenital Extreme Growth retardation
Abnormal dentition
Acanthosis Nigricans
Androgen Excess & Hypertrichosis
Gene involved Insulin receptor
Recessive

30. 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)

31. The key feature of all insulin resistance syndromes are acanthosis nigricans, androgen excess and massively raised insulin concentrations in the absence of obesity

32. Maternal transmission of mutated or deleted mitochondrial DNA (mtDNA) and the mitochondrial tRNA (leu(UUR)) gene (B) can result in maternally inherited diabetes.
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.

33. 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

34. Etiologic classification of DM (c’d) III. Other specific types
Endocrinopathies
Acromegaly
Cushing disease
Glucagonoma
Pheochromocytoma
Hyperthyroidism
Somatostatinoma
Aldosteronoma

35. Etiologic classification of DM (c’d) III. Other specific types
Infections
Congenital rubella
Cytomegalovirus
Hemolitic-uremic syndrome →→→

36. 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

37. Wolfram syndrome (DIDMOAD)
DI-diabetes insipidus
DM-diabetes mellitus
OA-optical atrophy
D- deafness

38. ????

39. Prader-Willi syndrome

40. Etiologic classification of DM (c’d) III. Other specific types
Gestational DM
Neonatal DM

41. 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.

42. Neonatal diabetes
Clinically two subgroups were recognized: transient neonatal diabetes mellitus (TNDM) & permanent neonatal diabetes mellitus (PNDM)

43. Transient neonatal diabetes
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 (range12-57 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

44. 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.

45. 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

46. 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

47. Ins is the major anabolic hormone of the body
Ins action is on target cells in tissues such as liver, adipocytes and muscle

49. 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

50. 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

51. 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

52. 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 counter-regulatory hormones

53. 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.

54. 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.

56. The hormonal interplay of Ins deficiency and glucagon excess shunts the free fatty acids to ketone body formation
Acetone
Acetoacetate
Β-oxyoil acid

57. 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

58. 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.

60. 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

63. 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

64. DM
Pyogenic skin infection are most uncommon as a presenting complaint, although vaginitis in teenage girls may be the presenting feature

65. 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

66. Hyperglycemia

67. Hyperglycemia

68. Clinical presentation
Polyuria
Polydipsia
Polyphagia
Weight loss
Lethargy
weakness
These symptoms may be present for days to weeks

69. Particularities DM in infants
Lability of the water & mineral metabolism
Stopping or loss body weight
Appetite increase or normal
Thirst, active sucking

70. Particularities DM in infants
Starch napkins or sticky stains due to glucosuria
Dry skin, ↓ turgor, skin infection

71. 2 types of DM manifestation in infants
First – acute onset, severe dehydration, intoxication, vomiting, coma as a toxico-infection shock
Second – dystrophy develops gradually, infection diseases connect
Ketonuria is absent to 4 mo old due to liver immaturity

72. Diagnosis of DM N.B! Additional: ↓ or absents of C-peptide
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

73. Criteria of DM compensation
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

74. Criteria of DM compensation (c’d) in childhood
Glucose level fasting 4-8 mmol/L
Glucose after feeding 10-11mmol/L ( mmol/L – less than renal threshold)
Night Glucose level 6-8 mmol/L
Episodes of Hypoglycemia are absent
Glucose absent in urine

75. 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

76. Differential Diagnosis
Diabetes Insipidus
Appendicitis
Fancony syndrome
Diabetes Mellitus type II

77. Factors influencing vasopressing secretion INCREASED SECRETION
Hypovolemia
Hyperosmolality
Upright position
Central hyperthermia
Stress and anxiety
Cerebral disease
Chest disease
Malignancies
Drugs (Carbamazepine, clofibrate Nicotine, angiotensin II Cholinergic drugs, Morphine, barbiturates)

78. Factors influencing vasopressing secretion DECREASED SECRETION
Hypervolemia
Hyperosmolality
Recumbent position
Central hyperthermia
Diabetes insipidus
Drugs & Alcohol (Dilantin, Anticholinergic agents)

79. POLYURIC CONDITIONS MIMICKING VASOPRESSIN DEFICIENCY
Physiologic suppression of vasopressin secretion
Psychogenic polydipsia
Organic polydipsia (hypothalamic disease)
Drug induced polydipsia (thioridazine, tricyclics)

80. 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

81. Diabetic ketoacidosis
Hyperglycemia
Ketonemia
Acidosis (pH≤7.3 & bicarbonate less than 15 mEq/L)
Glucosuria
Ketonuria

82. Complications of DM (acute)
Ketoacidosis, ketoacidotic coma
Dehydration
Nonketotic hyperosmolar coma
Hypoglicemia, hypoglicemic coma
Lactoacidotic coma

83. Complications of DM
Somogy phenomenon
Dawn phenomenon
Brittle Diabetes

84. Complications of DM (long-term)
Diabetic retinopathy
Diabetic nephropathy
Angiophathy of lower extremities
Diabetic neuropathy (periferal, central, autonomic)

85. Complications of DM (long-term)
Mauriac syndrome, Nobecur syndrome
Syndrome of limited joint mobility (hairopathy)
Skin pathology (lipoid necrobiosis, lipodystrophy, paronichia and etc)

86. lipoid necrosis's

87. lipoid necrobiosis

88. lipoid necrobiosis

89. Diabetes Mellitus in Children