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Diabetes Mellitus in Children DM Type I Olena Riga KhNMU.

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Presentation on theme: "Diabetes Mellitus in Children DM Type I Olena Riga KhNMU."— Presentation transcript:

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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 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

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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 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) Fist clinical description of the DM by Cels (30-50 yrs Anno Domini) The term “Diabayo” – passing through (30-90 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 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 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 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 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 yrs Klod Bernar discribed the pathogenesis of hyperglycemia 1869 yr medical student Paul Langerhans discovered the cells congestion in pancreas 1869 yr medical student Paul Langerhans discovered the cells congestion in pancreas 1874 yr Kussmaul discovered ketons, aceton, described specific type of breathing 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 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 1902 yr Opy – described the degeneration of the Langergans islet 1907 yr Lane Bersley (Chicago) discovered pancreatic cells type A and type B 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 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 A. Monogenic DM B. Exocrine pathology of pancreas C. Endocrine diseases D. Drugs E. 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 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 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.

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22 Manifestation of the DM if the % 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 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 Genetic defects in Ins action Type A Ins resistance Leprechaunism Rabson-Mendenhall syndrome Lipoatropic diabetes (Lorens syndrome)

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

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

28 Leprechaunism

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

30 Lipodystrophy Lorens syndrome Congenital or Adolescence Congenital or Adolescence Loss of subcutaneous fat – partial or total Loss of subcutaneous fat – partial or total Acanthosis Nigricans Acanthosis Nigricans Androgen Excess & Hypertrichosis Androgen Excess & Hypertrichosis Gene involved Total: Seipin & AGPAT2 (recessive) Partial :Lamin AC & PPARG (dominant) 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 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 mitochondrial myopathy Encephalopathy Encephalopathy lactic acidosis lactic acidosis stroke-like syndrome 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 Diseases of the exocrine pancreasPancreatitis Trauma, pancreatomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Pancreatic resection

34 Etiologic classification of DM (c’d) III. Other specific types Endocrinopathies EndocrinopathiesAcromegaly Cushing disease GlucagonomaPheochromocytomaHyperthyroidismSomatostatinomaAldosteronoma

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

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

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39 Prader-Willi syndrome

40 Etiologic classification of DM (c’d) III. Other specific types Gestational DM Gestational DM Neonatal 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. 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 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 anomalies on 6q24 locus DM associated within the first week and resolves around 12 weeks DM associated within the first week and resolves around 12 weeks 50% of cases DM will reoccur during the paediatric age range 50% of cases DM will reoccur during the paediatric age range Macroglossia seen in 23% Macroglossia seen in 23% Initial glucose values can be very high (range mmol/L) and so insulin is used initially although the dose can rapidly be reduced. Initial glucose values can be very high (range 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 The response to oral treatment such as sulphonylureas or metformin is uncertain

44 Permanent neonatal diabetes Kir6.2 mutations Kir6.2 mutations Only 10% have a remitting form of DM that may latter relapse Only 10% have a remitting form of DM that may latter relapse Most patients have isolated DM 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 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. 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 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 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

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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 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. 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. 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.

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

57 Accumulation of ketoacids results in metabolic acidosis and the compensatory rapid deep breathing, which is an attempt to excrete excess CO 2 (Kussmaul’s respiration) Accumulation of ketoacids results in metabolic acidosis and the compensatory rapid deep breathing, which is an attempt to excrete excess CO 2 (Kussmaul’s respiration) Acetone, formed by nonenzymatic conversation of acetoacetate, is responsible for the characteristic fruity odor of the breath 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) 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. With progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes imparired and ultimately results in coma.

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60 DM The loss of weight is on the basis of the catabolic state and urinary losses of calories due to polyuria 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 The no effective calories balance lead to the hunger & polyphagia (despite the increase food intake calories cannot be utilized) & weight loss occurs

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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 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 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 VomitingDehydration

66 Hyperglycemia

67 Hyperglycemia

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

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

70 Particularities DM in infants Starch napkins or sticky stains due to glucosuria Starch napkins or sticky stains due to glucosuria Dry skin, ↓ turgor, skin infection 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 First – acute onset, severe dehydration, intoxication, vomiting, coma as a toxico- infection shock Second – dystrophy develops gradually, infection diseases connect Second – dystrophy develops gradually, infection diseases connect Ketonuria is absent to 4 mo old due to liver immaturity Ketonuria is absent to 4 mo old due to liver immaturity

72 Diagnosis of DM N.B! Clinical presentation & paraclinic: hyperglicemia, glucosuria, ketonuria Clinical presentation & paraclinic: hyperglicemia, glucosuria, ketonuriaAdditional: ↓ or absents of C-peptide ↓ or absents of C-peptide ↑ glicolized Hb (HbAic) ↑ glicolized Hb (HbAic) ↑ fructosamine ↑ fructosamine presents of the antibodies to ß cells, Ins and to differens glutamatdecarboxilase isoformes 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 aim of treatment –”QULITY OF LIFE” The adequate growth & development of child The adequate growth & development of child Active social position in life & society Active social position in life & society Decreasing acute complication and prolong late complications of DM Decreasing acute complication and prolong late complications of DM Normal life duration Normal life duration

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

75 Criteria of DM compensation (c’d) Normal lipid, protein and mineral metabolism Normal lipid, protein and mineral metabolism HbAic, % HbAic, % Cholesterol mmol/L -< 5.2 Cholesterol mmol/L -< 5.2 Triglicerids mmol/L - < 1.7 Triglicerids mmol/L - < 1.7

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

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

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

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

80 POLYURIC CONDITIONS MIMICKING VASOPRESSIN DEFICIENCY Reduced renal responsiveness to vasopressin Reduced renal responsiveness to vasopressin Genetic: nephrogenic diabetes insipidus medullary cystic disease Genetic: nephrogenic diabetes insipidus medullary cystic disease Pharmacologic: lithium, demeclocycline, penthrane, diuretics Pharmacologic: lithium, demeclocycline, penthrane, diuretics Osmotic diuresis: diabetes mellitus reduced nephron population Osmotic diuresis: diabetes mellitus reduced nephron population Electrolyte disturbance: hypercalcemia hypokalemia Electrolyte disturbance: hypercalcemia hypokalemia Renal disease:postobstructive diuresis, renal tubular acidosis pyelonephritis, papillary necrosis, sickle cell disease Renal disease:postobstructive diuresis, renal tubular acidosis pyelonephritis, papillary necrosis, sickle cell disease Hemodynamic: hyperthyroidism Hemodynamic: hyperthyroidism

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

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

83 Complications of DM Somogy phenomenon Somogy phenomenon Dawn phenomenon Dawn phenomenon Brittle Diabetes Brittle Diabetes

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

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

86 lipoid necrosis's

87 lipoid necrobiosis

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89 Diabetes Mellitus in Children


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