DIABETES MELLITUS

1. DIABETES MELLITUS

2. DEFINITION a metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.

3. DIABETES EPIDEMIOLOGY • Diabetes is the most common endocrine problem worldwide. • Incidence of diabetes is alarmingly increasing all over the globe. • Incidence of childhood diabetes range between 3-50/100,000 worldwide

4. WHO CLASSIFICATION 2000 • Is based on etiology not on type of treatment or age of the patient. • Type 1 Diabetes (idiopathic or autoimmune b-cell destruction) • Type 2 Diabetes (defects in insulin secretion or action) • Other specific types

5. WHO CLASSIFICATION/2 • Both type 1 & type 2 can be further subdivided into: • Not insulin requiring • Insulin requiring for control • Insulin requiring for survival • Gestational diabetes is a separate entity • Impaired Glucose Tolerance (IGT) indicates blood glucose levels between normal & diabetic cut off points during glucose tolerance test.

6. DIAGNOSTIC CRITERIA • Fasting blood glucose level • Diabetic • Plasma >7.0 mmol • Capillary >6.0 mmol • IGT • Plasma 6.0-6.9 mmol • Capillary 5.6-6.0 mmol • 1 mg/dl = 0.05556 mmol/l • 2 hours after glucose load (Plasma or capillary BS) • IGT • 7.8-11.0 • Diabetic level • > 11.1 (200 mg)

7. Types of Diabetes in Children • Type 1 diabetes mellitus accounts for >90% of cases. • Type 2 diabetes is increasingly recognized in children with presentation like in adults. • Permanent neonatal diabetes • Transient neonatal diabetes • Maturity-onset diabetes of the young • Secondary diabetes e.g. in cystic fibrosis or Cushing syndrome.

8. MODY(Maturity onset diabetes of the young ) • Usually affects older children & adolescents • Not rare as previously considered • 5 subclasses are identified, one subclass has specific mode of inheritance (AD) • Not associated with immunologic or genetic markers • Insulin resistance is present

9. TRANSIENT NEONATAL DIABETES • Observed in both term & preterm babies, but more common in preterm • Caused by immaturity of islet b-cells • Polyuria & dehydration are prominent, but baby looks well & suck vigorously • Highly sensitive to insulin • Disappears in 4-6 weeks

10. PERMANENT NEONATAL DIABETES • A familial form of diabetes that appear shortly after birth & continue for life • The usual genetic & immunologic markers of Type 1 diabetes are absent • Insulin requiring, but ketosis resistant • Is often associated with other congenital anomalies & syndromes e.g. Wolcott-Rallison syndrome.

11. TYPE 1 DIABETES: ETIOLOGY • Type 1 diabetes mellitus is an autoimmune disease. • It is triggered by environmental factors in genetically susceptible individuals. • Both humoral & cell-mediated immunity are stimulated.

12. GENETIC FACTORS • Evidence of genetics is shown in • Ethnic differences • Familial clustering • High concordance rate in twins • Specific genetic markers • Higher incidence with genetic syndromes or chromosomal defects

13. AUTOIMMUNITY • Circulating antibodies against b-cells and insulin. • Immunofluorescent antibodies & lymphocyte infiltration around pancreatic islet cells. • Evidence of immune system activation. Circulating immune complexes with high IgA & low interferon levels. • Association with other autoimmune diseases.

14. ENVIRONMENTAL INFLUENCE • Seasonal & geographical variation. • Migrants take on risk of new home. • Evidence for rapid temporal changes. • Suspicion of environmental agents causing disease which is confirmed by case-control experimental animal studies.

15. ENVIRONMENTAL • Viruses • Coxasckie B • Mumps • Rubella • Reoviruses • Nutrition & dietary factors • Cow’s milk protein • Contaminated sea food

16. OTHER MODIFYING FACTORS • The counter-regulatory hormones: • glucagon • cortisol, • catecholamines • thyroxin, • GH & somatostatin • sex hormones • Emotional stress

17. ETIOLOGIC MODEL • The etiologic model of type 1 diabetes resembles that of Rheumatic fever. • Rheumatic fever was prevented by elimination of the triggering environ. factor (b-streptococci). • Similarly type 1 diabetes may be prevented by controlling the triggering factors in high risk persons.

18. CLINICAL PRESENTATIONS • Classical symptom triad: • polyuria, polydipsia and weight loss • DKA • Accidental diagnosis • Anorexia nervosa like illness

19. DIAGNOSIS • In symptomatic children a random plasma glucose >11 mmol (200 mg) is diagnostic. • A modified OGTT = oral glucose tolerance test (fasting & 2h) may be needed in asymptomatic children with hyperglycemia if the cause is not obvious. • Remember: acute infections in young non-diabetic children can cause hyperglycemia without ketoacidosis. • Children ingest 1.75 g/kg body weight in a similar volume of water by ratio (max 75 g as for adults).

20. Glycated haemoglobin • Although HbA1c testing is mainly used for monitoring blood sugar control in patients with diabetes, the WHO now recommends that HbA1c can be used as a diagnostic test for diabetes, provided that stringent quality assurance tests are in place and assays are standardised to criteria aligned to the international reference values. An HbA1c of 6.5% is recommended as the cut-off point for diagnosing diabetes. A value less than 6.5% does not exclude diabetes diagnosed using glucose tests.

21. NATURAL HISTORY • Diagnosis & initiation of insulin • Period of metabolic recovery • Honeymoon phase • State of total insulin dependency

22. METABOLIC RECOVERY During metabolic recovery the patient may Develop one or more of the following: • Hepatomegaly • Peripheral edema • Loss of hair • Problem with visual acuity These are caused by deposition of glycogen & metabolic re-balance.

23. HONEYMOON PERIOD • Due to b-cell reserve optimal function & initiation of insulin therapy. • Leads to normal blood glucose level without exogenous insulin. • Observed in 50-60% of newly diagnosed patients & it can last up to one year but it always ends. • Can confuse patients & parents if not educated about it early.

24. COMPLICATIONS OF DIABETES ARE NUTRITIONAL, METABOLIC AND CHRONIC DEGENERATIVE • Acute: • DKA (Diabetic ketoacidosis ) • Hypoglycemia • Late-onset: • Retinopathy • Neuropathy • Nephropathy • Ischemic heart disease & stroke

25. TREATMENT GOALS • Prevent death • Achieve biochemical control • Maintain growth and development • Prevent acute complications • Prevent or delay late-onset complications

26. TREATMENT ELEMENTS • Insulin therapy • Diet and meal planning • Exercise • Education • Monitoring • HbA1c every 2-months • Home regular BG monitoring • Home urine ketones tests when indicated

27. EDUCATION • Educate child & care givers about: • Diabetes • Insulin • Life-saving skills • Recognition of Hypo & DKA • Meal plan • Sick-day management

28. INSULIN • A polypeptide made of 2 b-chains. • Discovered by Bants & Best in 1921. • Animal types (porcine & bovine) were used before the introduction of human-like insulin (DNA-recombinant types). • Recently more potent insulin analogs are produced by changing aminoacid sequence.

29. FUNCTION OF INSULIN • Insulin being an anabolic hormone stimulates protein & fatty acids synthesis. • Insulin decreases blood sugar • By inhibiting hepatic glycogenolysis and gluconeogenesis. • By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue.

30. TYPES OF INSULIN • Short acting (neutral, soluble, regular) • Peak 2-3 hours & duration up to 8 hours • Intermediate acting • Isophane (peak 6-8 h & duration 16-24 h) • Biphasic (peak 4-6 h & duration 12-20 h) • Semilente (peak 5-7 h & duration 12-18 h) • Long acting (lente, ultralente & PZI) • Peak 8-14 h & duration 20-36 h

31. INSULIN CONCENTRATIONS • Insulin is available in different concentrations 40, 80 & 100 Unit/ml. • WHO now recommends U 100 to be the only used insulin to prevent confusion. • Special preparation for infusion pumps is soluble insulin 500 U/ml.

32. INSULIN REGIMENS • Twice daily: either NPH alone or NPH+SI. • Thrice daily: SI before each meal and NPH only before dinner. • Intensive 4 times/day: SI before meals + NPH or Glargine at bed time. • Continuous s/c infusion using pumps loaded with SI. • NPH insulin (or neutral protamineHagedorn) (also known as Humulin N, Novolin N, is an intermediate-actinginsulin • Insulin glargine, Lantus, is a long-acting basal insulinanaloguethat slowly release insulin, giving a long duration of action of 18 to 26 hours

33. INSULIN ANALOGS • Ultra short acting • Insulin Lispro • Insulin Aspart • Long acting without peak action to simulate normal basal insulin • Glargine

34. NEW INSULIN PREPARATIONS • Inhaled insulin proved to be effective & will be available within 2 years. • Nasal insulin was not successful because of variable nasal absorption. • Oral insulin preparations are under trials.

35. ADVERSE EFFECTS OF INSULIN • Hypoglycemia • Lipoatrophy • Lipohypertrophy • Obesity • Insulin allergy • Insulin antibodies • Insulin induced edema

36. PRACTICAL PROBLEMS • Non-availability of insulin in poor countries • injection sites & technique • Insulin storage & transfer • Mixing insulin preparations • Insulin & school hours • Adjusting insulin dose at home • Sick-day management • Recognition & Rx of hypo at home

37. DIET REGULATION • Regular meal plans with calorie exchange options are encouraged. • 45-50% of required energy to be obtained from complex carbohydrates, 20-25% proteins, 30% lipids • Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars. • Encouraged low salt, low saturated fats and high fiber diet.

38. CHILDREN NUMBER OF CALORIES/DAY = 1000 + (AGEx 100)

39. EXERCISE • Decreases insulin requirement in diabetic subjects by increasing both sensitivity of muscle cells to insulin & glucose utilization. • It can precipitate hypoglycemia in the unprepared diabetic patient. • It may worsen pre-existing diabetic retinopathy.

40. MONITORING • Compliance (check records) • HBG tests • HbA1 every 2 months • Insulin & meal plan • Growth & development • Well being & life style • School & hobbies

42. Pancreas & Islet Cell Transplantation • Pancreas transplants are usually given to diabetics with end stage renal disease. • Islet cell transplants, the ultimate treatment of type 1 diabetes is under trial in many centers in the US & Europe with encouraging results but graft rejection & recurrence of autoimmunity are serious limitations.

43. IMMUNE MODULATION • Immunosuppressive therapy for • Newly diagnosed • Prolonged the honey moon • For high risk children • Immune modulating drugs • Nicotinamide • mycophenolate

44. GENE THERAPY • Blocks the immunologic attack against islet-cells by DNA-plasmids encoding self antigen. • Gene encode cytokine inhibitors. • Modifying gene expressed islet-cell antigens like GAD.

45. PREDICTION OF DIABETES • Sensitive & specific immunologic markers • GAD Antibodies( Glutamic acid decarboxylase  antibodies) • GLIMA antibodies ( glycated islet cell • membrane–associated protein ) • IA-2 antibodies ( islet cell antibodies ) • insulin autoantibodies (IAAs), • Sensitive genetic markers • HLA haplotypes • DQ molecular markers

46. PREVENTION OF DIABETES • Primary prevention • Identification of diabetes gene • Tampering with the immune system • Elimination of environmental factor • Secondary prevention • Immunosuppressive therapy • Tertiary prevention • Tight metabolic control & good monitoring

47. Children and young people with type 1 diabetes should • be offered an ongoing integrated package of care by a • multidisciplinary paediatric diabetes care team. To optimisethe effectiveness of care and reduce the risk of complications,the diabetes care team should include members withappropriate training in clinical, educational, dietetic, lifestyle,mental health and foot care aspects of diabetes for children and young people.

48. Diabetic ketoacidosis (DKA)

49. POSITIVE DG OF DKA • History: polydipsia, polyuria • • Clinical: acidotic respiration • dehydration • drowsiness • abdominal pain/vomiting • • Biochemical: high blood glucose on finger-prick test • glucose and ketones in urine

50. Diabetic ketoacidosis (DKA) NICE guideline - Primary fluid replacement in DKA should be with isotonicsaline, not given too rapidly except in cases of circulatorycollapse. - Bicarbonate should not generally be used in the management of DKA. - Intravenous insulin should be given by infusion in cases of DKA.