Chapter 11. Prediction of Type 1A Diabetes: The Natural History of the Prediabetic Period

Transcription

1 Chapter 11 Prediction of Type 1A Diabetes: The Natural History of the Prediabetic Period

2 Greenbaum et al Diabetes June 11, 212 Fall in C peptide During First 2 Years From Diagnosis: Evidence of at Least Two Distinct Phases From Composite TrialNet Data.

3 Stages in Development of Type 1A Diabetes (?Precipitating Event) Beta cell mass Genetic Predisposition Overt immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present Minimal C-peptide Age (years) Eisenbarth 212

4 npod Tail: 12 yo 1 year diabetes -Lobular Pseudoatrophic Islets Glucagon/anti-CD3 Staining Insulin and Ki67 Staining

5 RISING HbA1c PRECEDES DIABETES HbA1c (%) Acute? HbA1c (%) Acute? HbA1c (%) HbA1c (%) Age (years) HbA1c (%) Age (years) Age (years) Age (years) Stene et al DAISY Study Pediatric Diabetes 7:

6 TRIGGERING QUESTIONS Is there an environmental trigger? Does autoantibody appearance mark triggering? Time lag between trigger and insulitis? Time lag between insulitis and beta cell killing? Best Model?Kilham Rat Virus (Multiple Other viruses) ACTIVATION INNATE IMMUNITY BY VIRUS SPECIFIC MHC AND SPECIFIC TCR (Mordes et al) ANTI-INFLAMMATORY PREVENTS (Zipris et al)

7 Non-Radioactive Electrochemiluminescent Insulin Autoantibody Assay Insulin Autoantibody Sulfo-TAG Labeled Proinsulin Biotin Labeled Proinsulin Streptavidin Coated plate Yu et al Diabetes Nov 211

8 Progression to Diabetes Among Children Positive for Anti-Islet Autoantibodies % NOT DIABETIC YEARS SINCE INITIAL AB+ TEST 1 Ab 2 Ab 3 Ab Steck et al Diabetes Care 211

9 Predicted Onset Age= *log(mean IAA) =.8* age first Ab+ Steck et al Diabetes Care 34: , 211

10 MEAN LOG IAA vs Time to DM from age Islet Ab first + Time to DM from age 1st Ab log1 Mean Insulin Abs R2=.37 P<.1 Steck et al Diabetes Care 211

11 GAD65 Levels with Years to Diabetes Mean GAD65 Levels (Log1) ICA512 Levels with Years to Diabetes Steck et al Diabetes Care Mean ICA512 Levels (Log1)

12 AGE DIABETES ONSET Age 1st Islet Ab+ vs Age DM Onset R2=.47 p< AGE 1st Islet Autoantibody + Steck et al Diabetes Care 211

13 Progressive Loss C-peptide Post Diagnosis (SEARCH Diab Care 29) DCCT Fast>=.23ng/ml

14 ACCELERATED LOSS OF PEAK C-PEPTIDE AFTER DIAGNOSIS OF TYPE 1A DIABETES ( WAITING FOR CONFIRMATORY ORAL GLUCOSE TOLERANCE TEST) Sosenko et al, Diabetes Care August 28

15 New Onset Type 1 DM: Loss of Insulin Secretion (ISR area(auc)) related to early (peak<45 min) versus delayed secretion Mixed Meal Steele et al Diabetes 53:26, 24

16 Type 1 diabetes risk stratification models based on islet autoantibody characteristics Model 1 Model 2 Model 3 Model 4 Stratification based on Number of islet autoantibodies (IAA, IA-2A, GADA) Stratification based on Stratification based on Stratification based on High titre of IAA (>3rd quart.) and IA-2A (>1st quart.) High risk characteristics: High titre IA-2A (>1st quart.) and IgG2 or IgG4 IA-2A and IgG2, IgG3 or IgG4 IAA Status of IA-2A and IA-2βA Category 1 One autoantibody Category 1 Neither IAA nor IA-2A at high titre Category 1 No high risk characteristic Category 1 IA-2A negative Category 2 Any two autoantibodies Category 2 One of IAA or IA-2A at high titre Category 2 One high risk characteristic Category 2 IA-2A positive and IA-2βA negative Category 3 All three autoantibodies Category 3 Both of IAA and IA-2A at high titre Category 3 Any two high risk characteristics Category 3 IA-2AβA positive Category 4 All three high risk characteristics Shaded Categories: 1-year diabetes risk >5% (high-risk categories) Achenbach et al., Diabetologia (26) 49:

17 Type 1 diabetes risk stratification considering changes in model risk category on follow-up Diabetes-free survival (%) Model 1 Model 2 Model 3 Model 4 P =.2 P <.1 P <.1 P <.1 P = Follow up (years) Stable low-risk category Stable high-risk category Changed from high-risk to low-risk category Changed from low-risk to high-risk category Achenbach et al., Diabetologia (26) 49:

18 Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Meier et al, Diabetologia 25 % Insulin/Pancreatic Area Diabetes Control

19 Time Course of Beta Cell Loss Linear, Chronic Model Eisenbarth (NEJM 1986, 314:136) Beta Cell Mass Age Benign:Malignant Model Lafferty (J Aut 1997, 1:261) Beta Cell Mass Benign Malignant Age Random Loss Model Palmer (Diabetes 1999, 48:17) Beta Cell Mass Age

20 Time Course Beta Cell Loss Linear: Eisenbarth NEJM 1986, 314:136 Prodrome> Acute Lafferty; J Aut 1997, 1:261 Random:Palmer Diabetes 1999, 48:17

21 Stages in Development of Type 1 Diabetes GENETICALLY AT RISK MULTIPLE ANTIBODY POSITIVE BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FIRST PHASE INSULIN RESPONSE PRE - DIABETES DIABETES J. Skyler TIME NEWLY DIAGNOSED DIABETES

22 T1DM- a slowly progressive T-cell mediated cell Mass?? 1% % Genetic susceptibility autoimmune illness Inciting Event(s) Silent Cell Loss Time (years) Diabetes Onset Islet Strong association with MHC class II (DQ in particular) Infectious Cell Other What associations is the agent(s)?- slope Etiology much of weaker, the cell if true? population loss? Environmental dependente.g. Is recovery insulin VNTR, possible toxin(s)? Mass CD152, once process other begins? Absence We cannot easily/accurately What underlies of childhood the measure effect illness? islet of age mass on slope in vivo or Iex vivo 5% Combination of factors? No accepted Age norm of of exposure? for cell the loss? islet number within a human pancreas Why does the cell destruction typically occur slowly (in contrast to graft rejection)? David Harlan Brittle Diabetes II III Is cell losscan Is cell cell mass exclusively regeneration completely immune mediated? occur? lost?

23 Diagnosis of Diabetes ADA NORMAL IMPAIRED DIABETES HbA1c < >=6.5 FASTING < 1 mg% (5.6 mm) >= 126 mg% (7 mm) ORAL GTT <14 mg% (7.8 mm) >=2 mg% (11.1 mm)

24 Gestational Diabetes (>=2 high) 1-g or 75-g Glucose mg/dl mmol/l 1-g Glucose Fasting h h h g Glucose Fsting h h

25 Stages in Development of Type 1A Diabetes (?Precipitating Event) Beta cell mass Genetic Predisposition Overt immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present No C-peptide Age (years)

26 Discordant Triplets at Risk for Diabetes Intravenous Glucose Tolerance Test (IVGTT) 1+3 minute insulin Antibody Positive Antibody Positive Initial Test DM Age Srikanta S. et al, New Engl J Med 38: , 1983

27 Biochemical Autoantibody Assays Insulin Glutamic Acid Decarboxylase ICA512 (IA-2)

28 DPT-1 Ancillary Biochemical Ab Cytoplasmic ICA Positive (3.4%) 1/2 Negative for GAD/ICA512/Insulin Ab.9% = 1 Biochemical Ab 1.1% >=2 Ab Cytoplasmic ICA Negative (96.6%) 3.3% =1 Biochemcial Ab.3% >=2 Ab Staging: Only 12% eligible ICA+/Bioch - Future Trials Likely without ICA

29 Progression to Diabetes vs Number of Autoantibodies (GAD, ICA512, Insulin) Percent not Diabetic Abs 2 Abs 1 Ab Years of Follow-up 3 Ab n = Abs n = Abs n = Verge et al. Diabetes, 1996;45;926

30 Gestational Diabetes: Risk at 2 years Type 1 Diabetes by Autoantibodies ICA, GAD65, ICA512(IA-2) Ab >=1 Ab 1 Ab 2 Ab 3 Ab Sensitivity GAD=63%; Sensitivity 3 Abs=82% Ziegler et al. Diabetes 1997: 46: , N=437

31 LADA: Latent Autoimmune Diabetes Adults in UKPDS study % GAD + Insulin by 6 Years ICA+ GAD65+ Ab AGE Turner et al. Lancet 1997;35:

32 Caveats of IVGTT Testing Caveat "First" Test lack response young children Lack Carbohydrate Type 1A and insulin resistance may coexist Can be <1 st Percentile in adults years prior to DM Subset normals <1 st % Variation e.g. puberty Suggestion Repeat Abnormal Tests Dietary Preparation similar to OGTT Subtract 2X fasting insulin Long-term follow up In absence Abs low risk Repeat tests; caution in interpreting changes

33 First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes (DPT) Chase et al. J. Peds 138,244; 2, Minute Insulin (uu/ml) ICA Negative ICA Positive AGE < BDC

34 FPIR in pre-diabetic relatives with initial FPIR > 5mU/L log FPIR (1+3' insulin) Years prior to diabetes Melbourne Pre-Diabetes Study (Colman PG & Harrison LC)

35 EARLY LOSS IVGTT ICA+ INFANTS: Individual insulin concentrations during IVGTTs performed to A) ICA negative children 1 5 years of age, B) ICA positive children who had not progressed to diabetes by May 21, and C) ICA positive children who had developed clinical Type I diabetes by May 21. (From: Keskinen P, Korhonen S, Kupila A, Veijola R, Erkkila S, Savolainen H, Arvilommi P, Simell T, Ilonen J, Knip M, Simell O: First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes. Diabetologia 45: , 22) 18 A B C Insulin (m U/l) Time (min)

36 Insulin Secretion (IVGTT) in Obese Child (BMI 3 to 35) Progressing to Diabetes: Type 1 + Type 2 with Elevated Fasting Insulin 25 Insulin (uu/ml) Insulin 2X Fast Age (years)

37 Lack of Progression to DM of ICA+ 62+ Relatives Percent Not Diabetic Years of Follow up

38 Number Abs: IVGTT > or <1st% Percent Not Diabetic Years of Followup 1Ab <1st 2Ab <1st 3Ab <1st 1Ab >1st 2Ab>1st 3Ab>1st

39 Melbourne Data: Dual Parameter Prediction Time to DM= ln(IVGTT)-.59ln(IAA) Percent Not Diabetic Predict<2.5 Predict> <2.5 N= Years of Follow up >2.5 N= Proc AAP:11:

40 DM Normal but increasing hemoglobin A1c levels predict progression from islet autoimmunity to overt type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). Stene Pediatr Diabet 25

41 Blood glucose values in Control vs. Daisy children Blood glucose, md/dl DAISY Control-FH Control no FH Barker et al. DiabetesCare, 24; 27:

42 Diabetes Autoimmunity Study in the Young General population cohort Sibling/offspring cohort screened = 21,713 enrolled = 293 high risk moderate risk average - low risk 41 1,69 All 693 relatives 1,491 1,7

43 DAISY Interviews and Clinical Interviews: diet infections immunizations allergies stress B 3m 6m 9m 1y 15m 2y 3y Visits Clinical Visits: blood sample for GAA, IAA, ICA512, ICA DNA throat and rectal swabs saliva sample

44 Prediction of Autoantibody Positivity and Progression to Type 1 Diabetes: DAISY study Barker et al. J Clin Endocrinol Metab 89:3896, Positive Of 1,972= 8.2% 1/3 5 False Confirmed + 5 Transient 58(4) Persistent 1/3 1/3 28 X1+ 24 Diabetic 22 >1+ 28 Not DM 1/3 of Multiple Time+ are Transient (22/( ) 2/3 High Risk Diabetes

45 DAISY AUTOANTIBODIES:Initial Test <Age 1 Percent with Persistent Autoantibodies (GAA/IAA/ICA512) 1 p<.1 3/4SOC /4NEC not 3/4SOC not 3/4NEC /4 SOC: /4 NEC: /4 SOC: /4 NEC: /27/97

46 Yu et al. JCEM 85: 2421, 2 Relatives (SOC) vs. Population (NEC) Persistent vs. Transient AutoAb 35 3 Percent SOC 3/4 SOC # 3/4 NEC 3/4 NEC #3/4 PERSISTENT TRANSIENT

47 PERCENT Affin>1(9) Multipe Abs f/u Diabetes Proinsulin High Risk "False Positive" Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. Achenbach et al, J.Clin Invest 24, 114:589

48 Candidate environmental causes of type 1 diabetes Definite (rare cases) congenital rubella Putative enteroviruses rotaviruses components of infant diet gluten cow s milk

49 Enteroviruses: Recent Studies Study Autoimmunity Diabetes Frisk 1992 Dahlquist 1995 CVB1-5 IgM CVB2-4 IgM Hyoty 1995 IgM,IgG CVB CVB IgM,IgG Clements 1995 Graves(DAISY) 1996,2 Hyoty (DIPP) 2 (<6mos.) No EV RNA (RNA 12%:18%) No EV IgM EV Ab:57%:31% EV RNA: 29% 6% EV RNA No EV RNA

50 Autoantibody development and enteroviral RNA SD score in a HLA-DR3/4,DQB1*32 sibling ECHO 16 GAA IAA ICA512 TGIgA DAISY ID EV- EV+ EV- EV+ EV+ EV- EV+ EV+ EV- EV- EV- Age [yrs]

51 Beta-cell autoimmunity and presence of enteroviral RNA in serum, saliva and stool Graves PM, DAISY, 1999 Prevalence of EV RNA 3% 2% 3/13 3/13 3/14 6/28 Cases Controls 1% % Relatives High risk children from the general population

52 DIPP Protocol Main Cohort (n=38,) Newborns screened for genetic risk High risk babies followed serially for ICA (n=81) ICA-positive children randomized to nasal insulin or placebo

53 Trials to Prevent Type 1 Diabetes Trialnet/DPT-1 ENDIT TRIGR DIPP

54 Development of islet autoantibodies in 161 offspring of mothers or fathers with T1D Cumulative Ab frequency (%) Age (years) Walter et al, Diabetologia 23 (updated 24) DR3/4-DQ8 DR4/4-DQ8 Moderate DR4-DQ8 Neutral Moderate DR3 Protective

55 Development of islet Abs - HLA DR-DQ and INS VNTR genotypes Cumulative Ab frequency (%) Age (years) P =.3 DR3/4-DQ8 or 4/4-DQ8 + INS VNTR I/I DR3/4-DQ8 or 4/4-DQ8 + INS VNTR I/III or III/III Other Walter et al, Diabetologia 23 (updated 24)

56 Development of islet Abs - proband Multiple autoantibodies (%) father only mother only Age (years) both parents or parent + sibling P <.1 P =.5 A. Ziegler

57 Progression from multiple islet Abs to diabetes - No effect of HLA DR-DQ or proband HLA Proband Type 1 diabetes (%) High Neutral or Protective Moderate Both parents or Parent plus sibling Mother only Father only Time from first autoantibody positive (years) A. Ziegler

58 Islet autoantibody appearance in BABYDIAB offspring 1 8 Any islet Abs (7.8%) 6 4 Multiple islet Abs (3.7%) Single islet Abs A. Ziegler Age (years) Hummel et al., Ann Intern Med, June 24

59 Progression to multiple Abs is necessary for disease 1 8 multiple antibodies Diabetes (%) Single IAA A. Ziegler Time from first Ab (years) Hummel et al., Ann Intern Med, June 24

60 Progression Insulin GAD IA-2 A. Ziegler

61 First antibody is insulin/proinsulin 8 Cumulative frequency (%) IAA GADA IA2A Age (years) A. Ziegler

62 IAA affinity is high in children who develop multiple islet Abs 1 12 P<.1 IAA Affinity (L/mol) multiple Abs IAA only Achenbach, J Clin Invest, 24 A. Ziegler

63 IAA affinity is relatively stable during follow-up 1 12 IAA Affinity (L/mol) Age (years) A. Ziegler

64 Progression to multiple islet autoantibodies in children is related to IAA affinity 1 IAA affinity high % with multiple islet abs IAA affinity low P = IAA positive follow-up (years) A. Ziegler

65 Risk for developing islet Abs in relation to birth autoantibody status in offspring of T1D mothers 1 % with multiple Abs P =.7 4 NEG GADA and IA2A at birth n = Father T1D POS GADA or IA2A at birth n = A. Ziegler Age (years) Koczwara et al, Diabetes 24