TYPE 1 DIABETES MELLITUS: AUTOIMMUNE DIABETES

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1 27 th Nov TYPE 1 DIABETES MELLITUS: AUTOIMMUNE DIABETES Bo Kyung Koo CONTENTS 1. Introduction on Type 1 diabetes (T1DM) 2. Pathogenesis of T1DM 3. Immunologic Markers in T1DM 4. Atypical 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 Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose stimulation of insulin secretion begins with its transport into the beta cell by a facilitative glucose transporter. Muscle 2

3 Diabetes Mellitus Definition of diabetes mellitus Metabolic abnormality characterized by hyperglycemia Diabetes mellitus = hyperglycemia Insulin Deficiency Insulin Resistance Overproduction of Glucose Discovery of Insulin 3

4 The Miracle of Insulin Banting, Best, and colleagues (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases. The first patient was treated in 1922 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 4

5 The worldwide incidence of childhood T1DM The DIAMOND Project Diabetic Medicine 2006 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 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 6

7 Temporal model for development of T1DM Individuals with a genetic predisposition are exposed to an immunologic trigger that initiates an autoimmune process gradual decline in beta cell mass The progressive impairment in insulin release results in diabetes when 80% of the beta cell mass is destroyed. 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 7

8 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 DR3: DRB1*0301, DR4: DRB1*0401 DR2: DR15 (DRB1*1501~5, 1507), DR16 (DRB1*1601, 1602, 1604) HLA DQ and T1DM Caucasian: DQA1*0301-DQB1*0302 (DQ8), DQA1*0501-DQB1*0201 (DQ2), DQA1*0301-DQB1*0201 African American: DQA1*0301-DQB1*0302 (DQ8), DQA1*0501-DQB1*0201 (DQ2), 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 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 8

9 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). CD95 ligand-expressing effector T cells Nature Reviews Immunology 7, (August 2007) 9

10 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). 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):

11 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 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

12 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; 12

13 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 13

14 By altering the immunoregulatory network of the host Through molecular mimicry 14

15 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 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 15

16 FINDIA Pilot Study (Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes) Arch Pediatr Adolesc Med. 2012;166(7): FINDIA Pilot Study (Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes) WHF: Whey-based hydrolyzed formula Whey-based FINDIA formula from which bovine insulin was removed (EP ) Arch Pediatr Adolesc Med. 2012;166(7):

17 The TRIGR Study JAMA. 2014;311(22): The TRIGR Study JAMA. 2014;311(22):

18 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 Curr Diab Rep (2015) 15: 86 18

19 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. The complete characterization of environmental factors that trigger beta-cell autoimmunity in genetically susceptible individuals remain elusive. Diagnosis Immunologic Markers in T1DM Prediction of the course of disease progression Prevention Treatment 19

20 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 Tertiary prevention of T1DM (phase II clinical trials) 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

21 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 1965 Phase 2, placebo-controlled, dose-escalation clinical trial 47 GADA-positive type 2 diabetic patients subcutaneous injections ofgad-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. 21

22 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 ofgad-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. Diabetes Prevention Trial Type 1 (DPT-1) oral insulin trial Time to Type 1 Diabetes from1994 to 2009 The entire DPT-1 population Subjects with a baseline IAA 80 uu/ml In subjects with a baseline confirmed IAA level 80 nu/ml, the annualized rate of type 1 diabetes development was 7.7% per year in the oral insulin group and 10.1% in the placebo group (HR 1.384, 95% CI ; P = 0.052). Diabetes Care 34: ,

23 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: CTLA4-Ig (Abatacept) Effector T cells are believed to play the final role in the autoimmune-mediated destruction of beta-cells associated with T1D. CTLA4 gene: associated with increased T1D risk CTLA4-Ig Inhibits co-stimulation (in effector T cell) a successful therapy for psoriasis 1 and rheumatoid arthritis Abrams JR, Lebwohl MG, Guzzo CA, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest. 1999;103: Genant HK, Peterfy CG, Westhovens R, et al. Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial. Ann Rheum Dis.2008;67:

24 CTLA4-Ig (Abatacept) The difference between groups was present throughout the trial, with an estimated 9 6 months delay (95% CI ) in C-peptide reduction with abatacept. Adjusted C-peptide AUC was 59% (95% CI ) higher at 2 years with abatacept (n=73) than with placebo (n=30, p=0.0029). Lancet 2011; 378: 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. 24

25 Clinical Course of T1DM LADA vs. Acute-onset T1DM Kim CS et al., Acta Diabetologia

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 No evidence of autoimmunity It accounts for 15 20% of T1DM with ketosis or ketoacidosis in Japan Imagawa A et al., NEJM 2000; Imagawa A et al., DiabetesCare 2003 CD3 T lymphocytes (green) and glucagon (red); A-D fulminant T1DM, G-H T1DM with GADA; Imagawa A et al., NEJM

27 Summary (IV) There is broad spectrum of T1DM spanning from fulminant T1DM to latent autoimmune diabetes in adults (LADA). LADA is characterized as autoimmune diabetes not requiring insulin at diagnosis. Fulminant T1DM is a rapidly progressing form of T1DM with no evidence of autoimmunity Fulminant T1DM is an important subtype of T1DM in Asian adults. Conclusions Type 1 diabetes is caused by autoimmune destruction of pancreatic β cells. Destruction of β cells is the result of a T lymphocyte mediated immune response. At least 20 different genes have been linked to T1DM and HLA gene has major effects. There are major autoantigenes: GAD65, IA-2 and ZnT8A Autoantibodies against these autoantigens appear years before clinical symptoms and are valuable markers for identifying high risk individuals. Intervention targeting auto-antigen or immune modulation is promising for prevention of T1DM. 27