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بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيم. Immunological markers in the pathogenesis of type 1 diabetes in Saudi children. Diabetes Mellitus (DM). Definition : a group of metabolic diseases that result from insulin deficiency, defect in insulin action, or both . DM is characterized by hyperglycemia

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بسم الله الرحمن الرحيم

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  1. بسم الله الرحمن الرحيم

  2. Immunological markers in the pathogenesis of type 1 diabetes in Saudi children

  3. Diabetes Mellitus (DM) Definition: a group of metabolic diseases that result from insulin deficiency, defect in insulin action, or both. • DM is characterized by hyperglycemia • patient may present with polyurea, polydipsia, weight loss, polyphagia, blurred vision.

  4. Etiological classification of diabetes mellitus Type 1 diabetes mellitus Type 2 diabetes mellitus Other specific types: Genetic defects of beta-cell function Infections Genetic defects in insulin action Uncommon forms of immune- Diseases of the exocrine pancreas medicated diabetes Endocrinopathies Other genetic syndromes Drug or chemical-induced sometimes associated with diabetes Gestational diabetes mellitus

  5. Type 1 Diabetes Mellitus • Forms 10% of diabetic cases • Chronic disease in children and young adults • >75% of type 1 DM patients develop • the disease before the age of 30 years. • High mortality • 95% are due to autoimmune destruction of • beta cells of the pancreas absolute (not relative) insulin deficiency

  6. Epidemiology • Type 1 diabetes incidence  through out the world by 2%/yr. • The incidence varies widely according to geographic location, • environment and genetic background of the population IDDM incidence in different countries per 100,000 / year

  7. Aetiology of Type 1 Diabetes Mellitus

  8. Objectives: a) To study the autoimmune pathogenesis of type 1 diabetes in Saudi children b) To establish the specialized tests for the detection of autoantibodies in type 1 diabetes c) To study 1st degree relatives of type 1 diabetes patients to establish the degree of risk due to the presence of these antibodies in genetically susceptible individuals

  9. Subjects: • Cross sectional study of the frequency of • autoimmune antibodies in type 1 diabetes • Children: • Al Sulaimania Hospital • King Khalid University Hospital • King Abdulaziz University Hospital • The inclusion criteria: • Saudi type 1 diabetes patient • Diagnosis based on the diagnostic criteria of the • Expert Committee of Diabetes on June 1997 • <15 yrs (diagnosis defined as the date when • insulin treatment first began)

  10. Study groups: • Type 1 diabetes patients, n= 194 • (93 boys; 101 girls) • Median age 6 yrs (1-17 yrs) • Newly diagnosed (< 3 months) • n =69 (34 boys; 35 girls.), • Median age 7 yrs; (1-13 yrs)

  11. Study groups . . . . . cont. 2.First Degree Relatives (n=60): Median age 7.5yrs (8/12 – 20 yrs) Inclusion criteria: Saudi Below 20 yrs No history of endocrine disease 3. Controls:n=50: Median age: 7 (1- 17 yrs)

  12. Methodology: • The questionnaire designed to show • the following: • 1) Duration of the disease • 2) Family history of the disease • 3) Rank of the patient between his siblings • 4) Season at time of diagnosis • 5) History of infection prior to diagnosis • 6) Household income of the family

  13. Methodology . . . . . cont. • Blood sample: • 5 mls collected in non-heparinized • (red top) tubes Serum is separated by centrifugation & stored at –20°C

  14. Methodology . . . . . cont. • Antibody assays: ELISA kits (Biomerica) to detect the 3 autoantibodies : • ICA (Islet cell antibody) • GADA (Glutamic acid decarboxylase) • IAA (Insulin autoantibody)

  15. Basic principle of ELISA • Microwells are coated with specific antigen • Serum which contain the antibodies was added and incubated 405nm  The wells were washed so what remains are the antigen-antibody complex  Conjugate was added which will bind with the complex formed is then read at 405nm  The resulting color

  16. Statistical Analysis: • Chi square and Fisher’s exact test, were used to determine distribution of individuals among groups. • Z-test of percents drawn from one sample and two samples. • P value <0.05 was considered significant.

  17. RESULTS

  18. Results: Results were grouped into: • Epidemiology • Frequency of autoantibodies in all • diabetic patients as compared to • controls • 3. Frequency of autoantibodies in newly • diagnosed patients • Frequency of autoantibodies in • relatives • 5. Special cases

  19. 1) The epidemiology of type 1 diabetes in Saudi children • Sex • Age • Income • Season • Ranking • Infection • Family history

  20. The sex distribution among Saudi • type 1 patients 194 101 (52%) (Girls) 93 (48%) (Boys)

  21. Age of onset of type 1 diabetes in • Saudi children Two peaks of disease incidence: First peak in early childhood (3- 4 yrs). Second peak at pubertal age (9-12 yrs)

  22. Seasonal variation in type 1 diabetes • onset • Important epidemiological factors in the incidence of • type 1 diabetes. • A winter peak in type 1 diabetes incidence was reported in • several Countries (Spain, Sweden, Jordan and the Sudan). Relation of onset of type 1 diabetes to environmental temperature Season Number Percentage Hot(summer) 58 48 Cold(winter) 40 32 Mild(spring, autumn) 27 22 Total177100

  23. d) The relation of birth order in the family and the risk of developing type 1 diabetes Number of earlier studies showed that first born child has a higher risk for type 1 diabetes. • Similar result was reported by Bingley et al. (2000).

  24. The role of recent infection in • precipitating type 1 diabetes • Viruses are primary suspected environmental • factors associated with diabetes. • Coxsackie virus was isolated from pancreas of • a 10 yrs old previously healthy boy, who • presented with diabetic ketoacidosis. • 1/3 of in-vitro rubella cases develop type 1 • diabetes. • The direct role of viruses in the destruction • of beta-cells is not yet known.

  25. Relation of onset of type 1 diabetes and history of recent infection (n=157 ) Similar result was also reported from Japan. While Venezuelan diabetic children gave history of infection prior to diagnosis.

  26. f) Relation of type 1 diabetes and monthly income of their families Risk of type 1 diabetes is related to social class ( Pop. Density; Educational Level; Residence and Income) Average family monthly Percentage income Number % < SR5000 64 36 SR5000 – < SR10000 65 36  SR10000 48 27 Total177100 Japan, USA and UK

  27. g) Risk of family members • Type 1 diabetes has an element of familial inheritance. • Monozygotic 25-60%, dizygotic twins 5-15%. • Risk among families is 5-15% , 0.4% in general • population. Relation Number Percentage Father 9 4.6 Mother 3 1.5 Siblings 20 10.0 Father & Sibling 3 1.5 Mother & Sibling 0 0.0 At least 1 affected relative 29 15.0

  28. ANTIBODY SCREENING

  29. Importance of autoantibodies: • The autoantibodies serve as a sensitive marker in prediction of type 1 diabetes. With predictive value reaching 100% for young siblings with high antibody titers. 2) They are more prevalent in healthy relatives of type 1 diabetes than the general population  they may provide clues to the etiology of the disease, thus contributing to the preventive or therapeutic modalities. 3) They confirm the autoimmune origins of the disease in patients who are difficult to categorize. So they improve the classification of diabetes.

  30. Diabetic autoantibodies • 1) ICA • 2) IAA • 3) GADA • IA2 antibodies • Heat-shock protein Ab • Carboxypeptidase H Ab

  31. Islet Cell Antibody (ICA): • ICA were first described in 1974 in 90% of • newly diagnosed type 1 diabetes patients. • ICA are formed against several islet antigens: • ganglioside, sulphatidase, sialoganglioside. • Immunohistochemical staining of cadaveric • pancreas by patient’s serum was the first • method. • Alternative method for ICA detection is ELISA. • Results: • ICA is present in 33% of the studied • population and in 6% of the control.

  32. 28% In newly diagnosed patients: • Previous study on Saudi type 1 diabetes: • a higher frequency of ICA (56%) • sample size was too small (n=16)

  33. Low frequency of ICA in newly diagnosed Saudi patient may be due to: • Low disease incidence in Saudi Arabia, • ( Japan ) • An ICA negative form of the disease. • Ethnic differences. • An early negative sero conversion. • Different testing technique.

  34. Insulin Autoantibodies (IAA): • Insulin is the only specific antigen in • diabetes. • IAA: defined as autoantibodies that bind • insulin and occur in insulin untreated • patients. • IAA is found in 35-70% of newly diagnosed • type 1 diabetes patients and is highest in • young individuals. • IAA can be measured by both RIA and • ELISA.

  35. 52% • Result Insulin Autoantibodies (IAA): • 70% of the study population • only2% of the control • Newly diagnosed is 52%

  36. Glutamic Acid Decarboxylase Ab (GADA): • GAD is an enzyme controlling the biosynthesis of • inhibitory neurotransmitter -amino butyric acid • (GABA). • GAD is present in  cells and other cells, but only • GAD extracted from brain and islets is recognized • by the sera of type 1 diabetes. • GADA found in (60-80%) of newly diagnosed type • 1 diabetic patient, and in less than 3% of control • subjects. • GADA is found in other diseases and it is not • transient antibody.

  37. 58% • Result:( GADA ) • GADA is present in 60% of the study population. • 58% of newly diagnosed

  38. The frequency of autoantibodies & age No statistical significant differences in the frequency of antibodies and different age groups.Similar to Swedish children. No relation between the frequency of the three autoantibodies and sex

  39. The frequency of autoantibodies and history of recent infection: Vahasalo et al (1996): infection during the preceding year increases the frequency of both ICA and IAA at diagnosis. Significant

  40. The frequency of autoantibodies and family history of type 1 diabetes: Similar negative finding was reported by Rewers and Norris (2002) for ICA and IAA.

  41. Frequency of autoantibodies and the duration of the disease • IAA frequency increases after • 3 months. • ICAs have the same frequency for • more than 3 years. • GADA increase after 3 years. • Similar results for ICA and GADA • (Savola et al., 1998).

  42. Causes of persistence autoantibodies with longer duration of the disease: • Slow process of  cell destruction. • Structural and/or functional mimicry • between exogenous proteins and • beta cell antigen or both. • Minimal scale, continuous cell • regeneration.

  43. Multiple autoantibodies: • One autoantibody is present in 32% • Two autoantibodies are present in 26% • Three autoantibodies are present in 17% • One or more autoantibodies are present • in 75% • literature reported higher value 90%

  44. Combination of autoantibodies: Antibodies No. of Cases Percent ICA 19 28 IAA 36 52 GADA 40 58 ICA and/or GAD 43 62 ICA and/or IAA 40 58 GAD and/or IAA 51 74 ICA and/or IAA and/or GADA 52 75

  45. Importance of combination of autoantibodies: • Combination of tests is more sensitive for • the prediction of type 1 diabetes than the • result of any single autoantibody. • These tests can be used successfully as • first line screening tests to detect high • risk individuals.

  46. FIRST DEGREE RELATIVES

  47. Relatives of patients with type 1 diabetes: • First degree relative have 15-20% greater • risk of developing type 1 diabetes than the • general population. • Family studies showed that majority of those relatives who developed diabetes were positive for autoantibodies.

  48. Relatives of patients with type 1 diabetes . . . . . cont. • Study and follow-up of first degree • relatives facilitate: • a) identification of pre-diabetic subjects • b)work out the predictive value of different • disease markers • c)understand the pathogenesis of type 1 • diabetes • d) encourage preventive measures.

  49. ICA in first degree relatives: • The risk of developing type 1 diabetes in • 10 yrs is 60-70% with higher ICA titer • (>80 JDFu). • ICA appears very early in life. • Due to difficulty in measuring ICA, it has • been replaced by other autoantibodies • combination.

  50. ICA in relatives: 15% • Higher than European values (8% in Finland and Germany). • Increase disease incidence in SA; • technique variation Kohner et al., 1995

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