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.

Every 10 seconds one patient die from DM 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

Mortality from DM type I Decrease on the 40%

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 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, 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)

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.

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 β-cells

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 80-90% betta cells were destructed

DM II type –resistant to Ins

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

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 & GH-resistence 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)

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. 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

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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 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

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.

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 counter-regulatory 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 toxico-infection shock Second – dystrophy develops gradually, infection diseases connect Ketonuria is absent to 4 mo old due to liver immaturity

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

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

Criteria of DM compensation (c’d) in childhood Glucose level fasting 4-8 mmol/L Glucose after feeding 10-11mmol/L (3.3-8.3 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 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