2Diabetes Mellitus in Children DM Type IOlena RigaKhNMU
3Diabetes MellitusDM 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.
4Every 10 seconds one patient die from DM World Statisticspatients with DM in the World were reiterated at 2006 yr– prognosis for 2025 yrEvery 10 seconds one patient die from DM
5World StatisticsEvery years the DM type I occurs in childrenEURODIAB: every year increasing DM type I in adults in 3% and in 4.8% in children
8Historical DataIncreasing of the urination was described 1500 yrs B.C. at EgyptFist 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
9Historical Data (c’d)1674 yr Tomas Willis (Oxford) supposed that the sugar pass to urine from bloodyrs Trommer and Felling – methodic of the definition of blood sugar by Copper Oxide1796 Rallo at first proposed to restrict the carbohydrate intake to patients with DM
10Historical Data (c’d)yrs Klod Bernar discribed the pathogenesis of hyperglycemia1869 yr medical student Paul Langerhans discovered the cells congestion in pancreas1874 yr Kussmaul discovered ketons, aceton, described specific type of breathing
11Historical Data (c’d)1989 yr Mering & Minkovsky established that the dogs with pancrectomy develops hyperglycemia and further death1902 yr Opy – described the degeneration of the Langergans islet1907 yr Lane Bersley (Chicago) discovered pancreatic cells type A and type B
12Historical Data (c’d)1955 yr Sanger (Cambridge) –discovery aminoacid structure in molecular of Ins
13С-peptide is the predecessor of Ins 1969 yr Steiner – invented biosynthesis of the C-peptide
15Etiologic 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)
16Etiologic classification of DM (c’d) III. Other specific types Monogenic DMExocrine pathology of pancreasEndocrine diseasesDrugsGenetics syndromes such as Down, Turner etc.
17The onset DM type I occurs predominantly in childhood, with median age of 7 to 15 yrs, but it may present at any age
18DM type IDM type I is characterized by autoimmune destruction of pancreatic β-cells
19DM type IΒ-cells destruction may be due to drugs, viruses, mitochondrial defects, ionizing radiation, etc
20DM (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 decarboxylaseDM I type is associated with other autoimmune diseases such as thyroiditis, Celiac disease, multiply sclerosis, Addison disease, and etc.
24Etiologic classification of DM (c’d) III. Other specific types Genetic defects of β-cell function chromosome 12, HNF-1ά - MODY-3chromosome 7, glucokinase, MODY-2chromosome 20, HNF-4ά - MODY-1Mitochondrial DNAMODY- maturity-onset diabetes of the young *HNF –hepatocyte nuclear factor gene mutation
25Etiologic classification of DM (c’d) III. Other specific types Genetic defects in Ins actionType A Ins resistanceLeprechaunismRabson-Mendenhall syndromeLipoatropic diabetes(Lorens syndrome)
26Type A Adolescence Ins-resistance in absence of obesity Acanthosis NigricansAndrogen Excess & HypertrichosisGene involved Insulin receptorRecessive
27Leprechaunism Congenital Abnormal faces Large genitalia SGA and growth retardationRarely survive infancyAcanthosis NigricansGene involved Insulin receptor & GH-resistenceRecessive
30Lipodystrophy Lorens syndrome Congenital or AdolescenceLoss of subcutaneous fat – partial or totalAcanthosis NigricansAndrogen Excess & HypertrichosisGene involved Total: Seipin & AGPAT2 (recessive) Partial :Lamin AC & PPARG (dominant)
31The key feature of all insulin resistance syndromes are acanthosis nigricans, androgen excess and massively raised insulin concentrations in the absence of obesity
32Maternal 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 myopathyEncephalopathylactic acidosisstroke-like syndromeMitochondrial 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.
33Etiologic classification of DM (c’d) III. Other specific types Diseases of the exocrine pancreasPancreatitisTrauma, pancreatomyNeoplasiaCystic fibrosisHemochromatosisFibrocalculous pancreatopathyPancreatic resection
34Etiologic classification of DM (c’d) III. Other specific types EndocrinopathiesAcromegalyCushing diseaseGlucagonomaPheochromocytomaHyperthyroidismSomatostatinomaAldosteronoma
35Etiologic classification of DM (c’d) III. Other specific types InfectionsCongenital rubellaCytomegalovirusHemolitic-uremic syndrome →→→
36Etiologic classification of DM (c’d) III. Other specific types Genetic syndromesDown syndromeKlinefelter syndromeWolfram syndromeFriedreich ataxiaHuntington choreaLaurence-Moon & Bardet-Biedl syndromeMyotonic distrophyPorphyriaPrader-Willi syndrome
40Etiologic classification of DM (c’d) III. Other specific types Gestational DMNeonatal DM
41Neonatal diabetesThere 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.
42Neonatal diabetesClinically two subgroups were recognized: transient neonatal diabetes mellitus (TNDM) & permanent neonatal diabetes mellitus (PNDM)
43Transient neonatal diabetes anomalies on 6q24 locusDM associated within the first week and resolves around 12 weeks50% of cases DM will reoccur during the paediatric age rangeMacroglossia 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
44Permanent neonatal diabetes Kir6.2 mutationsOnly 10% have a remitting form of DM that may latter relapseMost patients have isolated DM20% have developmental delay of motor and social function & generalized epilepsy so called DEND syndrome Developmental delay, Epilepsy and Neonatal DiabetesPatients 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.
45Etiologic classification of DM (c’d) III. Other specific types Drug- or chemical-inducedPentamidine, Nicotinic acidGlucocorticoidsThyroid hormoneß-adrenergic agonistsThiasidesΒ-Interferon & others
46InsulinIns 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
47Ins is the major anabolic hormone of the body Ins action is on target cells in tissues such as liver, adipocytes and muscle
49Metabolic events during the fed and fasted states (liver) High-Ins (fed) & Low Ins (fasted)stateGlucose uptake Glucose productionGlycogen synthesis GlycogenolysisAbsent gluconeogenesis Present G-sisLipogenesis Absent l-sisAbsent ketogenesis Ketogenesis
50Metabolic events during the fed and fasted states (muscle) High-Ins (fed) & Low Ins (fasted)stateGlucose uptake Absent glucose uptakeGlucose oxidation Fatty acid άketooxydationGlycogen synthesis GlycogenolysisProtein syntesis Proteolysis and amino acid release
51Metabolic events during the fed and fasted states (Adipose tissue) High-Ins (fed) & Low Ins (fasted)stateGlucose uptake Absent Glucose uptakeLipid synthesis Lipolysis and fatty acid releaseTriglyceride uptake Absent triglyceride uptake
52Pathophysiology 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
53Ins 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.
54Ins 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.
56The hormonal interplay of Ins deficiency and glucagon excess shunts the free fatty acids to ketone body formationAcetoneAcetoacetateΒ-oxyoil acid
57Accumulation 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
58Ketones 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.
60DMThe loss of weight is on the basis of the catabolic state and urinary losses of calories due to polyuriaThe no effective calories balance lead to the hunger & polyphagia (despite the increase food intake calories cannot be utilized) & weight loss occurs
63DMGlucosuria 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
64DMPyogenic skin infection are most uncommon as a presenting complaint, although vaginitis in teenage girls may be the presenting feature
65Clinical presentation About 30% of patients initially present with frank diabetic ketoacidosis:Air hungerKussmaul’s respirationAcetone on the breathObtundation of consciousness or comaVomitingDehydration
68Clinical presentation PolyuriaPolydipsiaPolyphagiaWeight lossLethargyweaknessThese symptoms may be present for days to weeks
69Particularities DM in infants Lability of the water & mineral metabolismStopping or loss body weightAppetite increase or normalThirst, active sucking
70Particularities DM in infants Starch napkins or sticky stains due to glucosuriaDry skin, ↓ turgor, skin infection
712 types of DM manifestation in infants First – acute onset, severe dehydration, intoxication, vomiting, coma as a toxico-infection shockSecond – dystrophy develops gradually, infection diseases connectKetonuria is absent to 4 mo old due to liver immaturity
72Diagnosis of DM N.B! Additional: ↓ or absents of C-peptide Clinical presentation & paraclinic: hyperglicemia, glucosuria, ketonuriaAdditional:↓ or absents of C-peptide↑ glicolized Hb (HbAic)↑ fructosaminepresents of the antibodies to ß cells, Ins and to differens glutamatdecarboxilase isoformes
73Criteria of DM compensation The aim of treatment –”QULITY OF LIFE”The adequate growth & development of childActive social position in life & societyDecreasing acute complication and prolong late complications of DMNormal life duration
74Criteria of DM compensation (c’d) in childhood Glucose level fasting 4-8 mmol/LGlucose after feeding 10-11mmol/L ( mmol/L – less than renal threshold)Night Glucose level 6-8 mmol/LEpisodes of Hypoglycemia are absentGlucose absent in urine
75Criteria of DM compensation (c’d) Normal lipid, protein and mineral metabolismHbAic, % - 5-7Cholesterol mmol/L -< 5.2Triglicerids mmol/L - < 1.7
76Differential Diagnosis Diabetes InsipidusAppendicitisFancony syndromeDiabetes Mellitus type II