الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

Immunological markers Immunological markers in the pathogenesis in the pathogenesis of type 1 diabetes in of type 1 diabetes in

Saudi childrenSaudi children

Diabetes Mellitus (DM)Diabetes Mellitus (DM)

DM is characterized by hyperglycemiaDM is characterized by hyperglycemiapatient may present with polyurea, patient may present with polyurea,

polydipsia, weight loss, polyphagia, polydipsia, weight loss, polyphagia,

blurred vision.blurred vision.

DefinitionDefinition: a group of metabolic diseases: a group of metabolic diseases

that result from insulin deficiency, defectthat result from insulin deficiency, defect

in insulin action, or bothin insulin action, or both..

Etiological classification of diabetesEtiological classification of diabetesmellitusmellitus

Type 1 diabetes mellitusType 1 diabetes mellitus

Type 2 diabetes mellitusType 2 diabetes mellitus

Other specific types:Other specific types: Genetic defects of beta-cell functionGenetic defects of beta-cell function InfectionsInfections Genetic defects in insulin actionGenetic defects in insulin action Uncommon forms of immune-Uncommon forms of immune- Diseases of the exocrine pancreasDiseases of the exocrine pancreas medicated diabetesmedicated diabetes EndocrinopathiesEndocrinopathies Other genetic syndromesOther genetic syndromes Drug or chemical-induced Drug or chemical-induced sometimes associated sometimes associated

with diabeteswith diabetesGestational diabetes mellitusGestational 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

Type 1 Diabetes MellitusType 1 Diabetes Mellitus

absolute (not relative) insulin deficiency

EpidemiologyEpidemiology• Type 1 diabetes incidence Type 1 diabetes incidence through out the world by through out the world by 2%/yr.2%/yr.• The incidence varies widely according to The incidence varies widely according to geographic geographic locationlocation,, environmentenvironment and and genetic backgroundgenetic background of the population of the population

0

5

10

15

20

25

30

35

Tota

l Inc

iden

ce

Finland Sweden Scotland Norway USA Denmark Holland New

Zealand

Canada England Poland France Mexico

IDDM incidence in different countriesIDDM incidence in different countriesper 100,000 / yearper 100,000 / year

Aetiology of Type 1 Diabetes MellitusAetiology of Type 1 Diabetes Mellitus

Objectives:Objectives:

b) To establish the specialized tests for theb) To establish the specialized tests for the detection of autoantibodies in type 1detection of autoantibodies in type 1 diabetesdiabetes

a) To study the autoimmune pathogenesisa) To study the autoimmune pathogenesis of type 1 diabetes in Saudi childrenof type 1 diabetes in Saudi children

c) To study 1c) To study 1stst degree relatives of type 1 degree relatives of type 1 diabetes patients to establish thediabetes patients to establish the degree of risk due to the presence ofdegree of risk due to the presence of these antibodies in genetically these antibodies in genetically susceptible individuals susceptible individuals

Subjects:Subjects:

The inclusion criteria:The inclusion criteria:1)1) Saudi type 1 diabetes patientSaudi type 1 diabetes patient2)2) Diagnosis based on the diagnostic criteria of theDiagnosis based on the diagnostic criteria of the Expert Committee of Diabetes on June 1997Expert Committee of Diabetes on June 19973)3) <15 yrs (diagnosis defined as the date when <15 yrs (diagnosis defined as the date when

insulin treatment first began)insulin treatment first began)

Cross sectional study of the frequency ofCross sectional study of the frequency ofautoimmune antibodies in type 1 diabetesautoimmune antibodies in type 1 diabetesChildren:Children:

• Al Sulaimania HospitalAl Sulaimania Hospital• King Khalid University HospitalKing Khalid University Hospital• King Abdulaziz University HospitalKing Abdulaziz University Hospital

• Newly diagnosed (< 3 months) Newly diagnosed (< 3 months)

n =n = 69 69 (34 boys; 35 girls.), (34 boys; 35 girls.),

Median age 7 yrs; (1-13 yrsMedian age 7 yrs; (1-13 yrs))

Study groups:Study groups:

1.1. Type 1 diabetes patients, Type 1 diabetes patients, n= 194n= 194 • (93 boys; 101 girls) (93 boys; 101 girls) • Median age 6 yrs (1-17 yrsMedian age 6 yrs (1-17 yrs) )

2.2. First Degree Relatives (n=60):First Degree Relatives (n=60): Median age 7.5yrs (8/12 – 20 yrs)Median age 7.5yrs (8/12 – 20 yrs)

Inclusion criteria:Inclusion criteria:

Saudi Saudi

Below 20 yrsBelow 20 yrs

No history of endocrine No history of endocrine diseasedisease

3. Controls:3. Controls: n=50:n=50:

Median age: 7 (1- 17 yrs)Median age: 7 (1- 17 yrs)

Study groups . . . . . cont.Study groups . . . . . cont.

Methodology:Methodology:

• The questionnaire designed to show The questionnaire designed to show the following:the following:

1) Duration of the disease1) Duration of the disease 2) Family history of the disease2) Family history of the disease 3) Rank of the patient between his 3) Rank of the patient between his siblingssiblings 4) Season at time of diagnosis4) Season at time of diagnosis 5) History of infection prior to 5) History of infection prior to diagnosisdiagnosis 6) Household income of the family6) Household income of the family

Methodology . . . . . cont.Methodology . . . . . cont.

Serum is separated by Serum is separated by centrifugation centrifugation & stored at –20°C & stored at –20°C

Blood sample:Blood sample: • 5 mls collected in non-heparinized 5 mls collected in non-heparinized

(red (red top)top) tubes tubes

• Antibody assays:Antibody assays:ELISA kits ELISA kits (Biomerica)(Biomerica) to detect the 3 to detect the 3 autoantibodiesautoantibodies : :

1)1) ICA (Islet cell antibody)ICA (Islet cell antibody)

2)2) GADA (Glutamic acid GADA (Glutamic acid decarboxylase)decarboxylase)

3)3) IAA (Insulin autoantibody)IAA (Insulin autoantibody)

Methodology . . . . . cont.Methodology . . . . . cont.

405nm405nm

Microwells are coated with Microwells are coated with specific antigenspecific antigen Serum which contain the Serum which contain the antibodies was addedantibodies was added and incubatedand incubated The wells were washed soThe wells were washed so what remains are thewhat remains are the antigen-antibodyantigen-antibody complexcomplex Conjugate was added whichConjugate was added which will bind with the complex formedwill bind with the complex formed is then read at 405nmis then read at 405nm The resulting colorThe resulting color

Basic principle of ELISABasic principle of ELISA

Statistical Analysis:Statistical Analysis:

Chi square and Fisher’s exact Chi square and Fisher’s exact test, were used to determine test, were used to determine distribution of individuals among distribution of individuals among groups.groups.

Z-test of percents drawn from Z-test of percents drawn from one sample and two samples.one sample and two samples.

P value <0.05 was considered P value <0.05 was considered significant.significant.

ResultResults:s:

1.1. EpidemiologyEpidemiology

2.2. Frequency of autoantibodies in allFrequency of autoantibodies in all

diabetic patients as compared todiabetic patients as compared to

controlscontrols

3. 3. Frequency of autoantibodies in newly Frequency of autoantibodies in newly

diagnosed patientsdiagnosed patients

4.4. Frequency of autoantibodies inFrequency of autoantibodies in

relativesrelatives

5. 5. Special casesSpecial cases

Results were grouped Results were grouped into:into:

1) The epidemiology of type 1 1) The epidemiology of type 1 diabetes in Saudi childrendiabetes in Saudi children

a)a) SexSex

b)b)AgeAge

c)c) IncomeIncome

d)d)SeasonSeason

e)e) RankingRanking

f)f) InfectionInfection

g)g)Family historyFamily history

a)a) The sex distribution among Saudi The sex distribution among Saudi type 1 patientstype 1 patients

101101(52%)(52%)(Girls)(Girls)

93 93 (48%)(48%)(Boys)(Boys)

194194

b)b) Age of onset of type 1 diabetes inAge of onset of type 1 diabetes in Saudi childrenSaudi children

Two peaks of disease incidence:Two peaks of disease incidence:First peak in early childhood (3- 4 yrs).First peak in early childhood (3- 4 yrs). Second peak at pubertal age (9-12 yrs)Second peak at pubertal age (9-12 yrs)

0

5

10

15

20

25

30

<1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15

Years

• Important epidemiological factors in the incidence ofImportant epidemiological factors in the incidence of type 1 diabetestype 1 diabetes.. • A winter peak in type 1 diabetes incidence was A winter peak in type 1 diabetes incidence was reported inreported in several Countries (Spain, Sweden, Jordan and the several Countries (Spain, Sweden, Jordan and the Sudan).Sudan).

c)c)Seasonal variation in type 1 Seasonal variation in type 1 diabetesdiabetes

onsetonset

SeasonSeason Number Number PercentagePercentage

HotHot (summer)(summer) 58 58 48 48

ColdCold (winter)(winter) 40 40 32 32

MildMild (spring, autumn)(spring, autumn) 27 27 22 22

TotalTotal 177177 100100

Relation of onset of type 1 diabetes to environmentalRelation of onset of type 1 diabetes to environmentaltemperaturetemperature

Number of earlier studies showed that first born Number of earlier studies showed that first born child has a higher risk for type 1 diabetes.child has a higher risk for type 1 diabetes.

• Similar result was reported by Bingley et al. Similar result was reported by Bingley et al. (2000).(2000).

d) The relation of birth order in the d) The relation of birth order in the family and the risk of developing type family and the risk of developing type 1 diabetes1 diabetes

0

10

20

30

40

50

60

70

80

90

100

1st child 2nd child 3rd child 4th child

• Viruses are primary suspected environmentalViruses are primary suspected environmental factors associated with factors associated with diabetesdiabetes..

• Coxsackie virus was isolated from pancreas ofCoxsackie virus was isolated from pancreas of a 10 yrs old previously healthy boy, who a 10 yrs old previously healthy boy, who presented with diabetic ketoacidosis.presented with diabetic ketoacidosis.

• 1/3 of 1/3 of in-vitroin-vitro rubella cases develop type 1 rubella cases develop type 1 diabetes.diabetes.

• The direct role of viruses in the destructionThe direct role of viruses in the destruction of beta-cells is not yet known.of beta-cells is not yet known.

e)e) The role of recent infection inThe role of recent infection in precipitating type 1 diabetes precipitating type 1 diabetes

Similar result was also reported from Japan. While Similar result was also reported from Japan. While Venezuelan diabetic children gave history of infection Venezuelan diabetic children gave history of infection prior to diagnosis.prior to diagnosis.

Relation of onset of type 1 Relation of onset of type 1 diabetes and history of recent diabetes and history of recent infection (n=157 )infection (n=157 )

0

10

20

30

40

50

60

70

80

Positive Negative

Risk of type 1 diabetes is related to social class ( Pop. Density;Risk of type 1 diabetes is related to social class ( Pop. Density;

Educational Level; Residence and Income)Educational Level; Residence and Income)

f) Relation of type 1 diabetes andf) Relation of type 1 diabetes and monthly income of their familiesmonthly income of their families

Average family monthlyAverage family monthly PercentagePercentage incomeincome NumberNumber % %

< SR5000< SR5000 64 64 36 36

SR5000 – < SR10000SR5000 – < SR10000 65 65 36 36 SR10000SR10000 48 48 27 27

TotalTotal 177177 100100

Japan, USA and UKJapan, USA and UK

Type 1 diabetes has an element of familial Type 1 diabetes has an element of familial inheritance.inheritance.• Monozygotic 25-60%, dizygotic twins 5-15%.Monozygotic 25-60%, dizygotic twins 5-15%.• Risk among families is 5-15% , 0.4% in generalRisk among families is 5-15% , 0.4% in general population.population.

g) Risk of family members g) Risk of family members

RelationRelation Number Number PercentagePercentage

FatherFather 9 9 4.6 4.6MotherMother 3 3 1.5 1.5SiblingsSiblings 20 20 10.0 10.0Father & SiblingFather & Sibling 3 3 1.5 1.5Mother & SiblingMother & Sibling 0 0 0.0 0.0At least 1 affectedAt least 1 affected relativerelative 29 29 15.0 15.0

Importance of autoantibodies:Importance of autoantibodies:

1)1) The autoantibodies serve as a sensitive The autoantibodies serve as a sensitive marker in prediction of type 1 diabetes. With marker in prediction of type 1 diabetes. With predictive value reaching 100% for young predictive value reaching 100% for young siblings with high antibody titers.siblings with high antibody titers.

2) They are more prevalent in healthy relatives 2) They are more prevalent in healthy relatives of type 1 diabetes than the general of type 1 diabetes than the general population population they may provide clues to the they may provide clues to the etiology of the disease, thus contributing to etiology of the disease, thus contributing to the preventive or therapeutic modalities.the preventive or therapeutic modalities.

3) They confirm the autoimmune origins of the 3) They confirm the autoimmune origins of the disease in patients who are difficult to disease in patients who are difficult to categorize. So they improve the classification categorize. So they improve the classification of diabetes.of diabetes.

Diabetic autoantibodiesDiabetic autoantibodies

1) 1) ICAICA2) IAA2) IAA3) GADA3) GADA4)4) IA2 antibodiesIA2 antibodies5)5) Heat-shock protein AbHeat-shock protein Ab6)6) Carboxypeptidase H AbCarboxypeptidase H Ab

• ICA were first described in 1974 in 90% ofICA were first described in 1974 in 90% of newly diagnosed type 1 diabetes patients.newly diagnosed type 1 diabetes patients.

• ICA are formed against several islet antigens:ICA are formed against several islet antigens: ganglioside, sulphatidase, sialoganglioside.ganglioside, sulphatidase, sialoganglioside.

• Immunohistochemical staining of cadavericImmunohistochemical staining of cadaveric pancreas by patient’s serum was the firstpancreas by patient’s serum was the first method.method.

• Alternative method for ICA detection is Alternative method for ICA detection is ELISAELISA..

Islet Cell Antibody (ICA):Islet Cell Antibody (ICA):

Results:Results:• ICA is present in 33% of the ICA is present in 33% of the studiedstudied population and in 6% of the population and in 6% of the control.control.

In newly diagnosed patients:In newly diagnosed patients:

• Previous study on Saudi type 1 Previous study on Saudi type 1 diabetes: diabetes:

•a higher frequency of ICA (56%) a higher frequency of ICA (56%) •sample size was too small (n=16)sample size was too small (n=16)

0

5

10

15

20

25

30

35

40

45

50

Control Patient

Positive

Negative

28%28%

Low frequency of ICA in newlyLow frequency of ICA in newlydiagnosed Saudi patient maydiagnosed Saudi patient maybe due to:be due to:

• Low disease incidence in Saudi Low disease incidence in Saudi Arabia,Arabia, ( Japan )( Japan )

• An ICA negative form of the disease.An ICA negative form of the disease.

• Ethnic differences.Ethnic differences.

• An early negative sero conversion.An early negative sero conversion.

• Different testing technique.Different testing technique.

• Insulin is the only specific antigen in diabetes.

Insulin Autoantibodies (IAA):Insulin Autoantibodies (IAA):

• 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.

Result Result Insulin Autoantibodies (IAA):Insulin Autoantibodies (IAA): • 70% of the study population70% of the study population• onlyonly 2% of the control2% of the control

• Newly diagnosed is 52%Newly diagnosed is 52%

0

5

10

15

20

25

30

35

40

45

50

Control Patient

Positive

Negative

52%52%

• GAD is an enzyme controlling the biosynthesis ofGAD is an enzyme controlling the biosynthesis of inhibitory neurotransmitter inhibitory neurotransmitter -amino butyric acid-amino butyric acid (GABA).(GABA).

Glutamic Acid Decarboxylase AbGlutamic Acid Decarboxylase Ab(GADA):(GADA):

• GAD is present in GAD is present in cells and other cells, but only cells and other cells, but only GAD extracted from brain and islets is recognizedGAD extracted from brain and islets is recognized by the sera of type 1 diabetes.by the sera of type 1 diabetes.

• GADA found in (60-80%) of newly diagnosed typeGADA found in (60-80%) of newly diagnosed type 1 diabetic patient, and in less than 3% of control1 diabetic patient, and in less than 3% of control subjects.subjects.

• GADA is found in other diseases and it is notGADA is found in other diseases and it is not transient antibody.transient antibody.

• 58% of newly 58% of newly diagnosed diagnosed

ResultResult:( GADA ):( GADA )• GADA is present in 60% of the study population.GADA is present in 60% of the study population.

0

5

10

15

20

25

30

35

40

45

50

Control Patient

Positive

Negative 58%58%

No statistical significant differences in the frequency No statistical significant differences in the frequency of antibodies and different age groups.of antibodies and different age groups. Similar to Similar to Swedish children.Swedish children.

The frequency of autoantibodies & The frequency of autoantibodies & ageage

0

10

20

30

40

50

60

70

80

90

100

110

ICA IAA GAD

<5

5-10

>10

No relation between the frequency of the three No relation between the frequency of the three autoantibodies and sexautoantibodies and sex

Vahasalo et al (1996): infection during the Vahasalo et al (1996): infection during the preceding year increases the frequency of both ICA preceding year increases the frequency of both ICA and IAA at diagnosis.and IAA at diagnosis.SignificantSignificant

The frequency of autoantibodies andThe frequency of autoantibodies andhistory of recent infection:history of recent infection:

0

10

20

30

40

50

60

70

80

90

100

110

ICA IAA GADA

positive

Negative

Similar negative finding was reported by Rewers and Similar negative finding was reported by Rewers and Norris (2002) for ICA and IAA. Norris (2002) for ICA and IAA.

The frequency of autoantibodies and The frequency of autoantibodies and family history of type 1 diabetes:family history of type 1 diabetes:

0

10

20

30

40

50

60

70

80

90

ICA IAA GADA

Positive

Negative

Frequency of autoantibodiesFrequency of autoantibodiesand the duration of the diseaseand the duration of the disease

• IAA frequency increases afterIAA frequency increases after 3 months.3 months.• ICAs have the same frequency forICAs have the same frequency for more than 3 years.more than 3 years.• GADA increase after 3 yearsGADA increase after 3 years..

• Similar results for ICA and GADA Similar results for ICA and GADA (Savola et al., 1998).(Savola et al., 1998).

• Slow process of Slow process of cell destruction. cell destruction.

Causes of persistence autoantibodiesCauses of persistence autoantibodieswith longer duration of the disease:with longer duration of the disease:

• Minimal scale, continuousMinimal scale, continuous cell cell regeneration.regeneration.

• Structural and/or functional mimicryStructural and/or functional mimicry between exogenous proteins and between exogenous proteins and beta cell antigen or both.beta cell antigen or both.

Multiple autoantibodies:Multiple autoantibodies:

• One autoantibody is present in 32%One autoantibody is present in 32%

• Two autoantibodies are present in Two autoantibodies are present in 26%26%

• Three autoantibodies are present in Three autoantibodies are present in 17%17%

• One or more autoantibodies are One or more autoantibodies are presentpresent

in in 75%75%

literature reported higher value literature reported higher value 90%90%

Combination of autoantibodies:Combination of autoantibodies:

AntibodiesAntibodies No. of Cases Percent No. of Cases Percent

ICAICA 19 19 28 28

IAAIAA 36 36 52 52

GADAGADA 40 40 58 58

ICA and/or GADICA and/or GAD 43 43 62 62

ICA and/or IAAICA and/or IAA 40 40 58 58

GAD and/or IAAGAD and/or IAA 51 51 74 74

ICA and/or IAA and/or GADA 52ICA and/or IAA and/or GADA 52 75 75

• Combination of tests is more sensitive forCombination of tests is more sensitive for the prediction of type 1 diabetes than thethe prediction of type 1 diabetes than the result of any single autoantibody.result of any single autoantibody.

• These tests can be used successfully asThese tests can be used successfully as first line screening tests to detect highfirst line screening tests to detect high risk individuals.risk individuals.

Importance of combination ofImportance of combination ofautoantibodies:autoantibodies:

• First degree relative have 15-20% greater First degree relative have 15-20% greater risk of developing type 1 diabetes than the risk of developing type 1 diabetes than the general population.general population.

Relatives of patients with type 1Relatives of patients with type 1diabetes:diabetes:

• Family studies showed that Family studies showed that majority of those relatives who majority of those relatives who developed diabetes were positive for developed diabetes were positive for autoantibodies.autoantibodies.

Relatives of patients with type 1 diabetes . . . . . cont.Relatives of patients with type 1 diabetes . . . . . cont.

• Study and follow-up of first degree Study and follow-up of first degree relatives facilitaterelatives facilitate::

a) a) identification of pre-diabetic subjectsidentification of pre-diabetic subjects

b)b) work out the predictive value of work out the predictive value of differentdifferent

disease markersdisease markers

c)c) understand the pathogenesis of type 1understand the pathogenesis of type 1 diabetesdiabetes

d) encourage preventive measures.d) encourage preventive measures.

• The risk of developing type 1 diabetes inThe risk of developing type 1 diabetes in 10 yrs is 60-70% with higher ICA titer10 yrs is 60-70% with higher ICA titer (>80 JDFu).(>80 JDFu).

• ICA appears very early in life. ICA appears very early in life.

• Due to difficulty in measuring ICA, it hasDue to difficulty in measuring ICA, it has been replaced by other autoantibodiesbeen replaced by other autoantibodies combination.combination.

ICA in first degree relatives:ICA in first degree relatives:

ICA in relatives:ICA in relatives:

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

0

10

20

30

40

50

60

70

80

90

100

Control Relative

Positive

Negative

15%15%

• The additional presence of IAA in non-diabetic The additional presence of IAA in non-diabetic relatives relatives positive for ICA positive for ICA the risk of developing the disease. the risk of developing the disease.• 70% of subjects positive for ICA and IAA are 70% of subjects positive for ICA and IAA are insulinopenic.insulinopenic.

IAA in relatives:IAA in relatives:

0

20

40

60

80

100

120

Control Relative

Positive

Negative

8%8%

• GADA has 41% positive predictive value.GADA has 41% positive predictive value.• It is detected several years before the It is detected several years before the clinical onsetclinical onset of the disease.of the disease.

GADA in relatives:GADA in relatives:

0

20

40

60

80

100

120

Control Relative

Positive

Negative

10%10%

The relation of frequency of The relation of frequency of autoantibodies with age in first-autoantibodies with age in first-degree relatives degree relatives

• Kulmala et al., 1998.Kulmala et al., 1998.

0

10

20

30

40

50

60

70

80

90

100

110

ICA IAA GAD

<5

5-10

>10

• 27% were positive for at least 1 27% were positive for at least 1 antibody. antibody. Higher than literature (Germany 12%; Italy Higher than literature (Germany 12%; Italy 14%)14%)

• Only 5% were positive for Only 5% were positive for multiplemultiple antibodies. antibodies. (Similar to European (Similar to European values)values)

Multiple autoantibodies in Multiple autoantibodies in first degree relatives first degree relatives

Case #1Case #15 yrs old male with an affected brother 5 yrs old male with an affected brother developed the disease, 3 months developed the disease, 3 months afterafter taking the first blood sample. taking the first blood sample. He was positive for IAA only.He was positive for IAA only. At time of diagnosis he also developed At time of diagnosis he also developed GADA.GADA.

During this study 2 relativesDuring this study 2 relativesdeveloped the diseasedeveloped the disease

Case #2Case #26 yrs old girl who developed the 6 yrs old girl who developed the disease 3 weeks disease 3 weeks afterafter taking the blood taking the blood samplesample. . Her blood sample was positive for IAA Her blood sample was positive for IAA and GADAand GADA. . This girl had an affected father, This girl had an affected father, brother, and two sisters. Her mother brother, and two sisters. Her mother also has hyperthyroidism.also has hyperthyroidism.

During this study 2 relativesDuring this study 2 relativesdeveloped the diseasedeveloped the disease

• Detection of autoantibodies in pre-diabetic and newlyDetection of autoantibodies in pre-diabetic and newly diagnosed patients facilitates the understanding of the diagnosed patients facilitates the understanding of the aetiopathogenesis of type 1 diabetes.aetiopathogenesis of type 1 diabetes.

• The frequency of the autoantibodies in the Saudi The frequency of the autoantibodies in the Saudi newly diagnosed patients were as follows: newly diagnosed patients were as follows:

ICA=28%;ICA=28%; GADA=58%;GADA=58%; IAA=52%.IAA=52%.

• The frequency of ICA was very low compared toThe frequency of ICA was very low compared to European value, while the others were within the European value, while the others were within the reported values. reported values.

Conclusions:Conclusions:

• 75% of the Saudi newly diagnosed type 1 75% of the Saudi newly diagnosed type 1 diabetesdiabetes expressed one or more of these expressed one or more of these autoantibodies atautoantibodies at time of diagnosis.time of diagnosis.

• The combination of IAA and GADA identified The combination of IAA and GADA identified 74%74% of the newly diagnosed patients.of the newly diagnosed patients.

• This combination improves the sensitivity of This combination improves the sensitivity of predicting type 1 diabetes among relatives predicting type 1 diabetes among relatives and theand the general population.general population.

• During this study, two siblings developed theDuring this study, two siblings developed the disease and both were positive for IAA and disease and both were positive for IAA and GADA.GADA.

Conclusion . . . . . cont.Conclusion . . . . . cont.

Recommendations:Recommendations:

• Establishment of a national data-Establishment of a national data-base base registry about type 1 diabetes in registry about type 1 diabetes in Saudi Arabia.Saudi Arabia.

• Screening of first degree relatives Screening of first degree relatives and and depending on the size of the depending on the size of the problem, problem, thereafter the general population.thereafter the general population.

• Selection of the sensitive Selection of the sensitive autoantibodyautoantibody combination, such as: combination, such as: IAA & IAA & GADAGADA, , added to it ICA or IA2 as a second added to it ICA or IA2 as a second stepstep for screening.for screening.

Recommendations . . . . . cont.Recommendations . . . . . cont.

• Repeated analysis to increase the Repeated analysis to increase the sensitivitysensitivity of autoantibody screening.of autoantibody screening.

• Follow-up of those at risk to find theFollow-up of those at risk to find the predictive valuepredictive value of each autoantibody of each autoantibody andand their combinationstheir combinations..

• All these data will be used for the All these data will be used for the planningplanning of future intervention trials.of future intervention trials.