TYPE 1 DIABETES MELLITUS: AUTOIMMUNE DIABETES

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1 Nov. 14th, 2014 TYPE 1 DIABETES MELLITUS: AUTOIMMUNE DIABETES Bo Kyung Koo CONTENTS 1. Introduction on Type 1 diabetes (T1DM) 2. Pathogenesis of T1DM 3. Immunologic Marker of T1DM 1

2 Diabetes Mellitus Comprised of a variety of disease all characterized by hyperglycemia and tissue changes that result from heterogeneous etiological and pathogenetic factors Stephen Fajans at his Banting Lecture Insulin Secretion & Action (GLUT) Pancreas Muscle 2

3 Discovery of Insulin The Miracle of Insulin Banting, Best, and colleagues went on to purify the hormone insulin from bovine pancreases. The first patient was treated in

4 Glucose Homeostasis 췌장 지방조직 인슐린인슐린글루카곤 간 근육 혈당이 180mg/dL 이상이되면콩팥에서당을재흡수하지못하고소변으로배출 소변에당이검출 공복혈당 신장 DeFronzo RA Ann Intern Med 1999, Wright EM AJPRP 2001 당뇨병 당뇨병의정의 고혈당을특징으로하는대사이상 당뇨병 = 고혈당 인슐린분비부족 인슐린작용이상 당의과잉생산 4

5 Classification of Diabetes Mellitus I. Type 1 diabetes (beta cell destruction, usually leading to absolute insulin deficiency) A. Immune mediated B. Idiopathic II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types A. Genetic defects of beta cell function B. Genetic defects in insulin action C. Disease of the exocrine pancreas D. Endocrinopathy E. Drug or chemical induced F. Infections G. Uncommon forms of immune mediated diabetes H. Other genetic syndromes associated with diabetes IV. Gestational diabetes mellitus Type 1 Diabetes Mellitus (T1DM) T1DM is the result of interactions of genetic, environmental, and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. Harrison's Principles of Internal Medicine, 18 th Ed. Inflammatory infiltrate of mononuclear cells in an islet from a 2-year old patient with type 1 diabetes of short duration. Mononuclear cells in and around islets are shown by yellow arrows. Gepts, W Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 14:

6 Pancreatic Islets within Pancreas Type 1 Diabetes Control Subjects Slides were stained for insulin (green), TUNEL (for apoptosis; red) and DAPI (for nuclei; blue), and images were taken at 200 magnification. Arrows indicate beta cell apoptosis Meier JJ et al., Diabetologia

7 Summary (I) Insulin plays a key role in glucose uptake and utilization and its homeostasis, which is crucial for life. T1DM is characterized by beta cell destruction, usually leading to absolute insulin deficiency. Type 1A. Immune mediated Type 1B. Idiopathic Temporal model for development of T1DM 7

8 Genetic Considerations The concordance of T1DM in identical twins ranges between 40 and 60% The major susceptibility gene for T1DM is located in the HLA region on chromosome 6. Account for 40 50% of the genetic risk of T1DM Encode the class II MHC molecules which present antigen to helper T cells Which HLA Loci are Involved? ?? + HLA DR and T1DM Alleles DR3 and DR4 associated with T1DM (Present in 95% of patients) DR3: freq. associated with other autoimmune disease DR3/DR4:most susceptible Allele DR2 protects against T1DM HLA DQ and T1DM Caucasian: DQA1*0301-DQB1*0302, DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0201 African American: DQA1*0301-DQB1*0302, DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0201 Asian : DQA1*0301-DQB1-0401, DQA1*0301-DQB1*0303 DQA1: arginine in position 52 DQB1: non-aspartic acid in position 57 8

9 Inherited Susceptibility Loci (Non-HLA loci) Genome association studies have identified at least 20 different genetic loci that contribute susceptibility to T1DM Mimi S. Kim Constantin Polychronakos, HorRes 2005 Inherited Susceptibility Loci LOCUS CHROMOSOME CANDIDATE GENES or MICROSATELLITES IDDM1 6p21 HLA-DQ\DR IDDM2 11p15 INS VNTR IDDM3 15q26 D15s107 IDDM4 11q13 MDU1, ZFM1, RT6, FADD/MORT1, LRP5 IDDM5 6q24-27 ESR, MnSOD IDDM6 18q12-q21 D18s487, D18s64, JK (Kidd locus) IDDM7 2q31 D2s152, IL-1, NEUROD, GALNT3 IDDM8 6q25-27 D6s264, D6s446, D6s281 IDDM9 3q21-25 D3s1303 IDDM10 10p11-q11 D10s193, D10s208, D10s588 IDDM11 14q24.3-q31 D14s67 IDDM12 2q33 CTLA-4, CD28 IDDM13 2q34 D2s137, D2s164, IGFBP2, IGFBP5 IDDM14? NCBI # 3413 IDDM15 6q21 D6s283, D6s434, D6s1580 IDDM16? NCBI # 3415 IDDM17 10q25 D10s1750-D10s1773 OTHERS 9

10 Temporal model for development of T1DM Breakdown in Immune Regulation Expansion of auto-reactive CD4+ and CD8+ T cells 1-3 Autoantibody-producing B lymphocytes 4-6 Activation of the innate immune system that collaborate to destroy the insulin producing β-cells 7-8. Nature 464, DiLorenzo, T. P.&Serreze, D. V. Immunol. Rev. 204, (2005); 2 Burton, A. R. et al. Diabetes 57, (2008); 3 Han, B. et al.j.clin. Invest. 115, (2005); 4. Serreze, D. V. et al. J. Immunol. 161, (1998); 5. Greeley, S. A. et al.nature Med. 8, (2002); 6. Hu, C. Y. et al. J. Clin. Invest. 117, (2007); 7.Zipris, D. et al. J. Immunol. 178, (2007); 8. Devendra, D. et al. Diabetes 54, (2005). 10

11 Nature Reviews Immunology 7, (August 2007) Immune System Balance - Imbalance of T reg cell to effector T cells A sequential loss of tolerance to multiple epitopes in disease progression Thymic T-cell negative selection related to insulin reactivity itself is key to the genetic predisposition towards the disease 1,2 Nature 464, Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, (1997). 2. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type I diabetes. Nature Genet. 15, (1997). 11

12 Previously reported Auto-antigen in T1DM Gene Symbol Protein Header Reference GAD2 glutamate decarboxylase 2 (pancreatic islets and brain, 65kDa) Baekkeskov et al.,1982 (1) INS insulin Palmer et al., 1983 (2) CA2 carbonic anhydrase II (CA2) Taniguchi et al., 2003 (3) DDC dopa decarboxylase (aromatic L-amino acid decarboxylase) Rorsman et al., 1995 (4) HSPD1 heat shock 60kDa protein 1 (chaperonin) Jones et al., 1990 (5) REG3A regenerating islet-derived 3 alpha Gurr et al., 2002 (6) SLC30A8 (ZnT8A) solute carrier family 30 (zinc transporter), member 8 Wenzlau et al., 2007 (7) ICA1 islet cell autoantigen 1 Bottazo et al., 1974 (8) PTPRN (IA-2A) protein tyrosine phosphatase, receptor type, N Rabin et al., 1994 (9) CPH carboxypeptidase H Castano et al., 1991 (10) PTPRN2 (IA-2β) protein tyrosine phosphatase, receptor type, N polypeptide 2 Kawasaki et al., 1996 (11) SLC2A2 solute carrier family 2 (facilitated glucose transporter), member 2 Inman et al., 1993 (12) TOP2A topoisomerase (DNA) II alpha 170kDa Chang et al., 1996 (13) 1.Baekkeskov S, et al. (1982) Nature 298(5870): ; 2. Palmer JP, et al. (1983)Science 222(4630): ; 3.Taniguchi T, et al. (2003) Pancreas 27(1):26-30; 4.Rorsman F, et al. (1995) Proc Natl Acad Sci U S A 92(19): ; 5.Jones DB, Hunter NR, & Duff GW (1990) Lancet 336(8715): ; 6. Gurr W, et al. (2002) Diabetes 51(2): ; 7.Wenzlau JM, et al. (2007) Proc Natl Acad Sci U S A 104(43): ; 8.Bottazzo GF, Florin-Christensen A, & Doniach D (1974)Lancet 2(7892): ; 9. Rabin DU, et al. (1994) J Immunol 152(6): ; 10.Castano L, Russo E, Zhou L, Lipes MA, & Eisenbarth GS (1991) J Clin Endocrinol Metab 73(6): ; 11. Kawasaki E, Hutton JC, & Eisenbarth GS (1996) Biochem Biophys Res Commun 227(2): ; 12. Inman LR, et al. (1993). Proc Natl Acad Sci U S A 90(4): ; 13. Chang YH, Hwang J, Shang HF, & Tsai ST (1996) Diabetes 45(4): T1D incidence is rising 3-5% per year Due to environmental cause(s) Incidence /100,000/ yr in children aged 0-14 Finland Sweden Colorado Germany REWERS 12

13 T1DM in Europe ~ ~ * Standardized incidence per 100,000 Patterson CC et al., Lancet 2009; *Bruno G et al., Diabetes 2010; TeeäärT et al., Pediatric Diabetes 2010 The worldwide incidence of childhood T1DM The DIAMOND Project Diabetic Medicine

14 Inverse Association between the Rise in Incidence Rate and the Average Rate Patterson CC et al., Lancet 2009 Environmental Factors Prenatal factors Genetic factor HLA genotype Perinatal and Intrauterine Factors Transplacental transmission of antibodies Birthweight 1 Cesarean deliveries 2 Interplay between maternal age and birth order Postnatal factors Breast-feeding 3,4 Cow s milk exposure 3,4 Vitamin D intake 5 Childhood infections 6,7 Obesity 8 Viral infections 9,10 Islet Autoimmunity 1 EURODIAB study group, Diabetes Care 2002; 2 Cardwell CR et al., Diabetologia2008; 3 Kostraba JN et al., Diabetes Care 1994; 4 Vaarala O et al,. J Allergy Clin Immunol 1995; 5 Ponsonby AL et al., Photochem Phtobiol2005; 6 Gale EA, Diabetologia 2002; 7 PengH et al., Rev Endocr Metab Disord2006; 8 FourlanosS et al., Diabetologia 2004; 9 Dahlquist G et al.,. Ann Med 1997; 10 McKinney PA et al, DiabMed2000; 14

15 The main putative environmental factors associated with the risk of T1DM Viral infection Dietary factors Bacteria Mumps virus Rubella virus Enterovirus/cocksakie B virus Cow s milk/bovine serum albumin Wheat proteins Vitamin D deficiency Direct cell killing Mimicry of cell autoantigenes Autoreactive T-cell activation and subsequent cell killing Triggering autoimmune response Mimicry of cell autoantigenes Triggering autoimmune response Lack of possible protective effect Environment al toxins Directly by replicating in and destroying beta cells 15

16 By altering the immunoregulatory network of the host Through molecular mimicry 16

17 Cow s milk and T1DM Structural similarity between BSA derived peptide called ABBOS* and an islet-cell autoantibody(ica69) Early introduction of cow s milk before gut maturation immune response against BSA *ABBOS: antibodies to a 17 a.a. section of the BSA 17

18 Infant diet and beta-cell autoimmunity Norris et al. DAISY 2000 Hazard Ratio 10 Prospective cohort study 27 cases and 1,022 controls 1 breast milk cow's milk meat fruits/veg. cereal gluten 0.1 Adjusted for HLA-DR,DQ and relationship to type 1 diabetic person TRIGR 3-yr Follow-up Results Seroconversion to 1+ Autoantibody 20% TRIGR: Trial to Reduce IDDM in the Genetically at Risk 15% 10% p=0.043 Cow's Milk Formula Casein Hydrolysate 5% n=173 0% Akerblom HK, Diabetologia

19 T lymphocytes (green) in an islet with beta cells (blue) of a patient with long-standing type 1 diabetes (age 42 years, diabetes duration 23 years) Meier et al,. Diabetologia 2005 Mark A Atkinson, George S Eisenbarth, Lancet 2001 Summary (II) Genetic, environmental, and immunologic factors involve in pathogenesis of T1DM. The major susceptibility gene for T1DM is located in the HLA region on chr6. DR3/DR4:most susceptible Auto-reactive T cells play a dominant role in disease initiation and progression. Autoantibodies against autoantigens appear years before clinical symptoms and are valuable markers for identifying high risk individuals 19

20 Diagnosis Immunologic Markers in T1DM Prediction of the course of disease progression Prevention Treatment Auto-antibodies in T1DM Glutamic acid decarboxylase (GAD65) autoantibodies (GADA) Islet cell auto-antibodies (ICA) Tyrosine phophatase like protein (IA-2A) Zinc transporter autoantibodies (ZnT8A) Bottazzo GF Lancet 1974 Steinunn Baekkeskov et al., Nature 1982 Rabin DU et al., J Immunol 1994 Wenzlau JM et al., PNAS 2007 Gepts W, Diabetes

21 Survival Distribution Function in Relation to the Number of Islet Autoantibodies The data in the figure shows that the number of islet autoantibodies determine the rate of progression to the clinical onset of type 1 diabetes mellitus (T1DM). The different lines for 1 4 islet autoantibodies indicates that few individuals with only one islet autoantibody develop T1DM within 5 years. By contrast, about 60% of individuals with four islet autoantibodies have developed T1DM within 5 years. Abbreviation: ab, autoantibody. Lernmark, Å. & Larsson, H. E. Nat. Rev. Endocrinol. 9, (2013); Anti-GAD65 antibodies (GADA) in T1DM Prevalence in T1DM: 65 75% 1,2 Predict the course of disease progression 3,4 alum-formulated recombinant human GAD65 Secondary/tertiary prevention of T1DM Positive effects in preserving residual C-peptide levels 5,6 1.Tridgell DM et al., Diabetes Care 2011, 2.Lampassona V et al., DiabetesCare Zampetti S et al., JCEM 2012, 4. Jin P et al., ClinEndocrinol 2011, 5. Ludvigsson J et al., NEJM 2008, 6 Agardg CD et al., Diabetologia

22 Anti-GAD Ab in Korean Type 2 Diabetic Patients Time-dependent changes in insulin dependency in anti-gad Ab (GADA) Lee SA et al., Diabetic Medicine 2011 Primary Prevention What to treat to prevent islet autoimmunity Avoid cow s milk protein 1 omega-3 fatty acids 2 Oral insulin Knip M et al., Am J Clin Nutr 2011; 2. Stene LC et al,. Am J clin Nutr 2003; 3. Achenbach P et al., Curr Diab Rep 2008; Nature 4. DPT 464, NEJM

23 Casein Hydrolysate or Conventional Cow s Milk-based Formula Diabetologia (2005) 48: Secondary Prevention Nonautoantigen Ciclosporin 1, BCG vaccine 2, Ketotifen 3 fail Autoantigen-specific Nasal insuiln 4 GAD Carel JC et al., J Autoimmun 1996; 2. Huppmann M et al., Diabetes Care 2005; 3. Bohmer K et al., Diabetes Care 1994; 4. Harrison LC et al., Diabetes Care 2004; 5 Agardh CD et al J Diabetes Complications Agardh CD et al Diabetologia2009; 7 Ludvigsson et al NEJM

24 placebo group 4 μg dose group Phase 2, placebo-controlled, dose-escalation clinical trial 47 GADA-positive type 2 diabetic patients 20 μg dose group 100 μg dose group subcutaneous injections of GAD-alum(4 [n=9], 20 [n=8], 100 [n=9] or 500 [n=8] μg) or placebo (n=13) at weeks 1 and 4 of the trial. GAD65 Antigen Therapy in Recently Diagnosed Type 1 Diabetes Mellitus 334 patients with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng/ml and detectable serum GAD65 autoantibodies Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. N Engl J Med 2012;366:

25 Tertiary Prevention: anti-cd20 Monoclonal Antibody Double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes N Engl J Med 2009;361: Targets of Immune Intervention in T1DM Nature 464,

26 The first case of fulminant type 1 diabetes in Korea A 36-yr-old woman presented with DKA at 36 wks of gestation. Duration of hyperglycemic symptoms < 2 weeks Glucose: 453 mg/dl (25.1 mmol/l) Arterial ph: 7.19 HbA1c: 5.8% C-peptide: 0.09 nmol/l Islet autoantibody: not determined Outcome: fetal demise Park CM et al. J Kor Diabetes Assoc 20:183~188, 1996 Fulminant T1DM A rapidly progressing form of T1DM Imagawa A et al., NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 2005 CD3 T lymphocytes (green) and glucagon (red); A-D fulminant T1DM, G-H T1DM with GADA; Imagawa A et al., NEJM

27 Fulminant T1DM Lack of autoimmunity It accounts for 15 20% of T1DM with ketosis or ketoacidosis in Japan Fulminant T1DM Autoimmune T1DM P values Age 39.1 ± ± 16.2 < BMI (kg/m 2 ) 20.7± ± 2.8 < FHx of T1DM 1/160 2/135 NS FHx of T2DM 25/119 33/102 NS Other autoimmune ds. 9/85 17/ Duration of Sx (days) 4.4 ± ± 25.1 NS BW loss 3.5 ± ± 3.7 < Flu-like Sx < Asso. with pregnancy GADA 7/145 (4.8%) 114/128 (89.1%) < Imagawa A et al., NEJM 2000; Imagawa A et al., DiabetesCare 2003; NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 2005 Autoimmunity in Newly Detected T1DM Newly diagnosed Type 1 diabetes (Jan 1999-Jul 2006) N = 99 Fulminant Type 1 diabetes N =7 (7.1%) Non-fulminant Type 1 diabetes N = 92 (92.9%) AutoAb (+) N = 68 (68.7%) AutoAb (-) N = 24 (24.2%) By retrieving data from the Seoul National University Hospital database, we identified all patients newly diagnosed with type 1 diabetes from January 1999 through July Cho YM et al., Diabetologia Nov;50(11):

28 Clinical Course of T1DM LADA in the Korean Population * 749 patients > 20 years of age who first visited the Diabetes Clinic of Seoul National University Hospital 527 patients with duration of diabetes <5 years without evidence of type 1 diabetes *Korean National Diabetes Program Park YS et al., Diabetes Metab Res Rev 2011 Hwangbo Y et al., Diabetes Metab J

29 Summary (III) Immunologic marker might be useful for diagnosis, prediction of prognosis and prevention in T1DM. Intervention targeting auto-antigen or immune modulation is promising for prevention of T1DM. Nature and mechanism of β-cell destruction in human seems to be variable, which results in a broad spectrum of T1DM spanning from fulminant T1DM to LADA. Conclusions T1DM is characterized by beta cell destruction, usually leading to absolute insulin deficiency. Genetic, environmental, and immunologic factors involve in pathogenesis of T1DM. Auto-reactive T cells play a dominant role in disease initiation and progression. Presence of atypical type of T1DM, such as fulminant T1DM(a rapidly progressing T1DM without evidence of autoimmunity) call for further investigations on pathogenesis of T1DM. 29