Diabetes in Children & Adolescents

1. In The Name Of GOD Diabetes in Children &Adolescents

2. Agenda • 1-Epidemiology • 2-Definition • 3-Pathogenesis • 4-Classifications • 5-Other types of DM in children • 6-Diagnosis & assessment • 7-treatment • 8-Special considerations (sick day, surgery, exercise) • 9-Associated conditions • 10-Complications

3. Epidemiology • Diabetes mellitus is a devastating disease that, according to the WHO, is expected to affect the lives of 380 million people by the year 2025. • It is also estimated that 5% of all deaths in the world are caused by diabetes. • The number of patients will increase by 50% in the next 10 years. • Of concern, both T1D and T2D are increasing in youth and presenting at younger ages, implying a longer burden of disease and earlier onset of vascular complications.

4. Epidemiology • Type 1 diabetes accounts for over 90% of childhood and adolescent diabetes. • Although less than half of individuals with type 1 diabetes are diagnosed before the age of 15 years . • Mean annual incidence rates for childhood type 1 diabetes (0–14 years age group) (0.1 to 57.6 per 100,000) • A seasonal variation in the presentation of new cases is well described, with the peak being in the winter months

5. Epidemiology • There is no recognizable pattern of inheritance. • The risk of diabetes to an identical twin of a patient with type 1 diabetes is about 36% • For a sibling the risk is approximately 4% by age 20 years and 9.6% by age 60 years, compared with 0.5 % for the general population. • The risk is higher in siblings of probands diagnosed at younger age • Type 1 diabetes is 2–3 times more common in the offspring of diabetic men (3.6–8.5%) compared with diabetic women (1.3–3.6%)

6. Definitions

7. Definitions

8. Definitions • In children and adolescents the A1C is not a criteria for diagnose of DM or IFG/IGT. • Recent studies question the validity of A1C in diagnosis of DM in pediatric population, and suggest OGTT or FPG as more suitable diagnostic tests. • OGTT should be done with 1.75 g/kg (up to 75 g) in children to diagnose DM. • In the absence of symptoms, hyperglycemia detected under conditions of acute infective, traumatic, or other stress may be transitory. • An OGTT should not be performed if diabetes can be diagnosed using fasting, random or post-prandial criteria as excessive hyperglycemia can result.

9. Pathogenesis • Most cases are due to T-cell mediated pancreatic islet ß-cell destruction. • Serological markers of an autoimmune pathologic process, including islet cell, GAD, IA-2 (Islet tyrosine phosphatase), IA- 2ß, or insulin autoantibodies, are present in 85-90% of individuals. • Clinical symptoms appear when approximately 90% of pancreatic beta cells are destroyed .

10. Pathogenesis • More than 40 distinct genomic locations provided evidence for association with T1D. • 40–50% of genetic predisposition on short arm of chromosome 6, Class II HLA region of the major histo-compatibility complex (MHC) • Whites HLA-DR3 or HLA-DR4, Blacks HLA-DR7, Japanese HLA-DR9. HLA-DR2 seems protective • 11 other loci, chromosome 11 (INS-VNTR), T-cell activation and regulation genes (CTLA-4), protein tyrosine phosphatase N22 (PTPN22), genes in interleukin pathway (IL-2R) ,…

11. Pathogenesis • The environmental triggers (chemical and/or viral) which initiate pancreatic beta cell destruction remain largely unknown, but the process usually begins months to years before the manifestation of clinical symptoms. • Enterovirusinfection has been associated with development of diabetes associated autoantibodies . • studies have shown that high birth weight is followed by an increased risk of type 1 diabetes in later life. • Studies indicate that rapid weight gain during the first year of life is a risk factor for type 1 Diabetes.

12. Pathogenesis • Vitamin D supplementation is associated with a lower incidence of type 1 diabetes (24 and 33 per 100 000 years at risk, respectively) as compared with those who did not (204 per 100 000 years at risk). • In addition, children who had a dose of 2000 IU daily had a decreased frequency of type 1 diabetes. • Low vitamin D, calcium, or dairy is as associated with greater prevalence of DM-2 or metabolic syndrome. • Vitamin D deficiency contributes to impaired insulin secretion and probably insulin action. • Vitamin D receptors have also been identified in cells of the immune system • The greatest increase in blood sugar was noted in those with 25 (OH) D levels below 40 nmol/L.

13. Classification • Diabetes can be classified into four clinical categories: • 1-Type 1 diabetes (due to β-cell destruction, usually leading to absolute insulin deficiency) • 2- Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) • 3- Other specific types of diabetes( e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced ) • 4- Gestational diabetes mellitus (GDM) (diabetes diagnosed during pregnancy that is not clearly overt diabetes) • Some patients cannot be clearly classified as type 1 or type 2 diabetic

14. Classification • I. Type 1 • ß -cell destruction, usually leading to absolute insulin deficiency: • A. Immune mediated • B. Idiopathic • II. Type 2 • May range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance

15. Classification III. Other specific types • A. Monogenic defects of ß -cell function (MODY) • 1. Chromosome 12, HNF-1a (MODY3) • 2. Chromosome 7, glucokinase (MODY2) • 3. Chromosome 20, HNF-4a (MODY1) • 4.Chromosome 13, insulin promoter factor; IPF-1 (MODY4) • 5. Chromosome 17, HNF-1ß (MODY5) • 6. Chromosome 2, NeuroD1 (MODY6) • 7. Mitochondrial DNA mutation • 8. Chromosome 7, KCNJ11 (Kir6.2) • 9. Others

16. Classification III. Other specific types • B. Genetic defects in insulin action • 1. Type A insulin resistance • 2. Leprechaunism • 3. Rabson-Mendenhall syndrome • 4. Lipoatrophic diabetes • 5. Others

17. Classification III. Other specific types • C. Diseases of the exocrine pancreas • 1. Pancreatitis • 2. Trauma / pancreatectomy • 3. Neoplasia • 4. Cystic fibrosis • 5. Hemochromatosis • 6. Fibrocalculous pancreatopathy (in sever malnutrition) • 7. Others

18. Classification III. Other specific types • D. Endocrinopathies • 1. Acromegaly • 2. Cushing’s syndrome • 3. Glucagonoma • 4. Phaeochromocytoma • 5. Hyperthyroidism • 6. Somatostatinoma • 7. Aldosteronoma • 8. Others

19. Classification III. Other specific types • E. Drug- or chemical-induced • 1. Vacor • 2. Pentamidine • 3. Nicotinic acid • 4. Glucocorticoids • 5. Thyroid hormone • 6. Diazoxide • 7. ß-adrenergic agonists • 8. Thiazides • 9. Dilantin • 10. α-Interferon

20. Classification III. Other specific types • Viruses • Coxaschie B • Mumps • Rubella • Reoviruses • Congenital rubella • Cytomegalovirus

21. Classification III. Other specific types • G. Uncommon forms of immune-mediated diabetes • 1. ‘‘Stiff-man’’ syndrome • 2. Anti-insulin receptor antibodies • 3. Polyendocrine autoimmune deficiencies APS I and II • 4.Others

22. Classification III. Other specific types • H. Other genetic syndromes associated with diabetes • 1. Down syndrome • 2. Klinefelter syndrome • 3. Turner syndrome • 4. Wolfram syndrome • 5. Friedreich’s ataxia • 6. Huntington’s chorea • 7. Laurence-Moon-Biedl syndrome • 8. Myotonic dystrophy • 9. Porphyria • 10. Prader-Willi syndrome

23. T2DM in children • T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance. • in > 75% of cases in youth there is a first or second-degree relative with T2DM. • with a sex ratio (male: female) varies from 1:4–1:6 • • without associated HLA specificities. • • without associated islet cell autoimmunity • T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD)]

24. T2DM in children • Testing for type 2 diabetes in asymptomatic children* • I-Overweight (BMI≥85th percentile ) • Plus any two of the following risk factors: • 1- Family history of type 2 diabetes in first- or second-degree relative • 2- Race/ethnicity (Native American, African American, Latino,) • 3- Signs of insulin resistance or conditions associated with insulin resistance (acanthosisnigricans, hypertension, dyslipidemia, polycystic ovarian syndrome, or SGA) • 4- Maternal history of diabetes or GDM during the child’s gestation • Age of initiation: age≥ 10 years or at onset of puberty, if puberty occurs at a younger age • Frequency: every 3 years ADA . 2014

25. Autoimmune T2DM (LADA) • The pathophysiology is unclear. • It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. • It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells . • in younger adult patients (25–34 years), resulting in more rapid development of insulin dependence, usually by 3 years duration • The presence of islet cell antibodies (ICA) and GAD antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults or LADA.

26. Autoimmune T2DM (LADA) • Diabetes autoantibody testing also should be con- sidered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss, keto- sis/ketoacidosis), some of whom may have T2DM. • Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM.

27. Management of Type 2 • Lifestyle change should be the first step • Moderate exercise ≥ 60 min/d and < 2 h/d non- academic screen time) • The first medication used should be metformin. • Start at low dose (500 mg/d) due to possible GI effects. • It has the advantage over sulfonylureas of similar reduction in HbA1c without the risk of hypoglycemia. • Failure of mono therapy with metformin over 3 months indicates the need to add sulfonylurea, or insulin alone or in combination.

28. Management of Type 2

29. Monogenic diabetes • MODY was originally described as a disorder with the following characteristics: • onset before 25 years of age, • obesity is unusual • Autosomal dominant inheritance. • Non-ketotic diabetes mellitus. • No need to insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis • Not progressive, or slowly progressive and hyperglycemia responsive to diet or drugs for years to decades. • Must be diabetes in one parent (2 generations) and ideally a grandparent or child ( 3 generations)

30. Monogenic diabetes • Chromosome 12, HNF-1a (MODY3) • 2. Chromosome 7, glucokinase (MODY2) • 3. Chromosome 20, HNF-4a (MODY1) • 4.Chromosome 13, insulin promoter factor; IPF-1 (MODY4) • 5. Chromosome 17, HNF-1ß (MODY5) • 6. Chromosome 2, NeuroD1 (MODY6) • HNFs, IPF-1 α, and NEUROD 1 regulates the genes and synthesis of proteins like insulin gene, Krebs cycle enzymes and GLUTs. Glucokinase is expressed in β-cells and liver. It is Glucose sensor” in β-cells • In all MODYs pharmacological treatment is needed( except in MODY2). • SUR is the drug of choice for MODY

31. Monogenic diabetes

32. The β-Cell & MODY-Related Proteins

33. Neonatal diabetes • This rare condition (1 in 400,000 births) • DM diagnose within first 6 months of life. • May be associated with IUGR • There are 2 types: • 1-TNDM: which resolved at median 12 weeks • Approximately half of the cases are transient have been associated with paternal isodisomy and other imprinting defects of chromosome 6,( ZAC and HYAMI gene on 6q24) or mutation of HNF-1ß, SUR1 (ABCC8), and sometimes Kir6.2. • There are higher risk of ( up to 50% ) relapse diabetes may appear later in life.

35. Neonatal diabetes • 2-PNDM : which required lifelong treatment • Mutation in KCNJ11 gene encoding Kir6.2 subunit of K-ATP channel or mutation in SUR1 (ABCC8), Glucokinase, INS, FOXP3, IPF-1, PTF1A. • Activating mutations of KCNJ11, which is the gene encoding the ATP-Sensitive Potassium Channel Subunit Kir6.2 (7p15-p13) • Mutations of the Insulin Promoter Factor-1 (chromosome7) in which there is pancreatic aplasia. • Homozygote glucokinase deficiency (chromosome 7) • Mutations of the FOXP3 gene (T cell regulatory gene) as part of the IPEX syndrome

36. Mitochondrial diabetes • sensorineural deafness is common and is characterized by progressive non-autoimmune beta-cell failure. • Maternal transmission of mutated mitochondrial DNA (mtDNA) can result in maternally inherited diabetes. • Point substitution of nucleotide in position 3243 (A to G) in Mito-t-RNA (Leu UUR gene) is the most common cause. • Around 1-1.5% of type 2 DM population are MID.

37. Mitochondrial DM • The range of age of onset is very wide, usually presents in early adulthood • The clinical presentation is variable , it may mimic type 1 or type 2 DM. • The mechanism possibly associated with gluco-sensoric function impairment and decreased insulin secretion of β-cell. • There are also some degree of pancreas atrophy. • In some patients insulin therapy is needed but in others maybe diet alone is enough. • Metformin is contraindicated in MIDD because of potential risk of lactic acidosis.

38. Drug induced diabetes • 1-In neurosurgery: large doses of dexamethasone • 2-In oncology: L-asparaginase, high dose glucocorticoids, cyclosporine or tacrolimus may be associated with diabetes. L-asparaginase usually causes a reversible form of diabetes. Tacrolimus and cyclosporine may cause a permanent form of diabetes. • Often the diabetes is cyclical and associated with the chemotherapy cycles, • 3-Following transplantation, the use of high dose steroids and tacrolimus; • 4- Diabetes can also be induced by the use of atypical antipsychotics including olanzapine (Zyprexa), risperidol (Risperdal), quetiapine (Seroquel), and ziprasidone (Geodon)

39. Stress hyperglycemia • Stress hyperglycemia has been reported in up to 5% of children presenting to an emergency department. • Acute illness or injury; traumatic injuries, febrile seizures and elevated body temperature (>39 degrees). • The reported incidence of progression to overt diabetes varies from 0% to 32%. • Children with incidental hyperglycemia without a serious concomitant illness were more likely to develop diabetes than those with a serious illness .

40. T1 DM in children

41. Insulin therapy • Pharmacokinetics of Available Insulin Products

42. Insulin regimens. • I-Two injections daily: • of a mixture of short or rapid and intermediate acting insulin (before breakfast and the main evening meal). Children on twice daily regimens often require more (perhaps two-thirds) of their total daily insulin in the morning and less (perhaps 1/3) in the evening. • II-Three injections daily: • using a mixture of short or rapid and intermediate acting insulin before breakfast; rapid or regular insulin alone before afternoon snack or the main evening meal; intermediate acting insulin before bed or variations of this. • III- Basal-bolus regimen • of the total daily insulin requirements, 40–60% should be basal insulin, the rest pre-prandial rapid-acting or regular insulin.

43. Insulin regimens. Breakfast Lunch Dinner Aspart Aspart Aspart Lispro Lispro Lispro Glulysene Glulysine Glulysine Plasma insulin Glargine or Detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

44. Insulin regimens. • • Glargine can be given before breakfast, before dinner or at bedtime with equal effect, but nocturnal hypoglycemia occurs significantly less often after breakfast injection • Glargine is often given once a day, but many children may need to be injected twice a day • When transferring to glargine as basal insulin, the total dose of basal insulin needs to be reduced by approximately 20% to avoid hypoglycemia. • Detemir is most commonly given twice daily in children When transferring to detemir from NPH, the same doses can be used to start with.

45. Glycemic targets

46. Guide to adjusting insulin dosage

47. Insulin regimens. • Blood glucose levels tend to rise in the hours of the morning (usually after 0500 hours) prior to waking. This is called the dawn phenomenon. • In non-diabetic individuals the mechanisms include increased nocturnal growth hormone secretion, increased resistance to insulin action and increased hepatic glucose production. • These mechanisms are more potent in puberty. • Morning hyperglycemia can in some cases be preceded by nighttime hypoglycemia called Somogi phenomenon

48. Assessment and monitoring • Measurement is best determined by self-monitoring of blood glucose(SMBG) in theses situations: • Pre- and post-meals, bedtime (7 tests/day) • Pre-meals, bedtime (4 tests/day) • When symptoms of hypoglycaemia occur • When a top-up dose of insulin is needed • Urinary glucose reflects glycemic levels over the preceding several hours and is affected by the renal threshold for glucose, around 10–11 mmol/L (180–200 mg/dl). • Urine Glc has uncertain correlation with BG levels; • Inability to detect hypoglycemia or monitor response to treatment of hypoglycemia;

49. Assessment and monitoring • Monitoring of urinary or blood ketones: • Urine or blood ketone measurement should be monitored during hyperglycemia, sick days, and impending ketoacidosis . • A urinary ketone reading of • <0.5 mmol/L is normal, and no action is needed. • 0.5–1.5 mmol/L( trace) : Give additional s.c. injection of a rapid-acting insulin if BG is elevated to 10 mmol/L (180 mg/dL) or above. • 1.5–3.0 mmol/L(moderate): High risk of ketoacidosis, but usually can be managed with oral fluids and s.c injection of a rapid-acting insulin diabetes • >3.0 mmol/L(large) is usually accompanied by acidosis. Urgent contact Emergency Department (E.D.) is needed.

50. Assessment and monitoring • HbA1c • Glucose irreversibly attached to the hemoglobin during the life cycle of the circulating red cell (which is approximately 120 d) forming glycated hemoglobin. • HbA1c reflects levels of glycemia over the preceding 4–12 wk, the most recent week is not included because the most recent glycation is reversible HbA1c.