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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.

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Diabetes Mellitus in Children

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  1. Diabetes Mellitus in Children DMType I Olena Riga KhNMU

  2. 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.

  3. World Statistics 246.000.000patients 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

  4. 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

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

  6. 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

  7. 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

  8. Historical Data (c’d) • 1813-1878 yrs Klod Bernar discribed the pathogenesis of hyperglycemia • 1869 yr medical studentPaul Langerhans discovered the cells congestion in pancreas • 1874 yr Kussmaul discovered ketons, aceton, described specific type of breathing

  9. 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

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

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

  12. 1973 yr mono component - Ins was synthesized

  13. 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)

  14. 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.

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

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

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

  18. 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.

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

  20. DM II type –resistant to Ins

  21. 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

  22. 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)

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

  24. Leprechaunism • Congenital • Abnormal faces • Large genitalia • SGA and growth retardation • Rarely survive infancy • Acanthosis Nigricans • Gene involvedInsulin receptor & GH-resistence • Recessive

  25. Leprechaunism

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

  27. LipodystrophyLorens syndrome • Congenital or Adolescence • Loss of subcutaneous fat – partial or total • Acanthosis Nigricans • Androgen Excess & Hypertrichosis • Gene involvedTotal: Seipin & AGPAT2(recessive) Partial :Lamin AC & PPARG (dominant)

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

  29. 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.

  30. 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

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

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

  33. 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

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

  35. ????

  36. Prader-Willi syndrome

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

  38. 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.

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

  40. 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

  41. 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.

  42. 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

  43. 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

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

  45. 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

  46. 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

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