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Differentiation of Diabetes by Pathophysiology, Natural History

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Differentiation of Diabetes by Pathophysiology, Natural History 8/14/2016 1990 Type 2 Differentiation of Diabetes by Pathophysiology, LADA Natural History and TypeTyp 1 Prognosis LADA: Latent autoimmune diabetes in adults Diabetes prevalence 3% Do we know what diabetes is? 2015 1921 Diagnosed by Type 2 ?? Diabetes mellitus measuring one metabolite- glucose LADA Type 1 Diabetes prevalence 0.1% Diabetes prevalence 7% 1960 Stages of Type 2 Diabetes 100 Adult Onset 75 50 Type 2 Diabetes 25 Phase III Type 2 Type 2 Postprandial IGT Diabetes Diabetes Hyperglycemia Phase I Phase II Juvenile 0 Onset –12 –10 –6 –2 0 2 6 10 14 Diabetes prevalence 1.5% Years From Diagnosis Reprinted with permission from Lebovitz H. Diabetes Reviews. 1999;7:139 1 8/14/2016 Proposed Stage 1 Stage 2 Stage 3 Why Change the T1D Diagnostic Criteria? Nomenclature Beta Cell Beta Cell Beta Cell Provides a framework to inform benefit/risk evaluation Phenotypic Autoimmunity Autoimmunity Autoimmunity Characteristics Normoglycemia Dysglycemia Dysglycemia for regulatory, reimbursement, and clinical care with Presymptomatic Presymptomatic Symptomatic Phase in Natural interventions to prevent symptomatic T1D History Improves the design of prevention trials Catalyzes risk screening and increases enrollment in natural history and prevention clinical trials Earlier diagnosis has current benefits – Decreased risk of DKA and hospitalization at diagnosis – Greater levels of residual functional beta cell mass at time of initiation of insulin replacement may lead to long-term benefit Early Stages of Type 1 Diabetes: + Diagnostic Criteria Environment Genes (e.g. vi ruses, microbiome, epigenetics, physical activity, dietary factors) Stage #1 Stage #2 Stage #3 Stage Autoimmunity Autoimmunity New Onset Normoglycemia Dysglycemia Symptomatic T1D Inflammation and autoimmunity Inflammation and metabolic stress Presymptomatic Presymptomatic Beta Cell Destruction Beta Cell Dysfunction .Multiple AutoAbs .Dysglycemia: Impaired Glucose Hyperglycemia Tolerance and/or Impaired Fasting Glucose Diabetes (Type 1, Type 2, Other Forms) .Multiple AutoAbs • FPG ≥100 mg/dL or Complications Diagnostic .No impaired ≥110mg/dL .Clinical Symptoms Criteria glucose tolerance • OGTT: 2h PG ≥140mg/dL; 30, or impaired fasting 60, 90 min PG >200 mg/dL glucose • Random plasma glucose >200 mg/dL Microvascular Complications Macrovascular Complications • HbA1c >5.7%; >5.9% Retinopathy Coronary Artery Disease Nephropathy Periperal Arterial Disease • Increasing HbA1c (10%) Neuropathy Stroke 11 T1D incidence is Rising 3-5% per Year Islet Autoantibodies in T1D Incidence /100,000/ yr in children 0-14 yr 1st generation assays 60 Finland Insulin autoantibodies 50 ICA 40 Sweden 30 Colorado 2nd generation (RIA, ELISA) ZnT8A IA-2A GADA mIAA 20 Germany Poland 10 33rdrdgenerationgeneration ECL ECL-IA-2A ECL-GADA ECL-IAA ElectroChemiLuminescent(ECL, etc. ) 0 1950 1960 1970 1980 1990 2000 2 8/14/2016 Progression to Stage 3 Symptomatic T1D in At-Risk Children HbA1c increases prior to diagnosis in children Stratified for Number of Islet Autoantibodies with multiple islet autoantibodies. 100 (0) (1) 80 No. of islet autoantibodies 60 None 1 Islet diabetes (%) 40 2 Islet 3 Islet Proportion withoutProportion 1 type 20 (2) 0 (3) 0 5 10 15 20 No. of events Islet autoantibodies, No. Age (years) 3 Islet 358 250 112 20 2 Islet 227 168 82 19 1 1 Islet 474 430 272 118 9 None 12318 8875 5253 1161 44 JAMA. 2013;309(23):2473-2479 Olli Helminen et al. Diabetes 2015;64:1719-1727 Impact of age on risk for disease progression in antibody-positive relatives participating in TrialNet Pathway to Prevention Study Type 1 Diabetes Risk Screening: Stage 1 to Stage 3 Stage 2 to Stage 3 Screening for Stage 1 . Relatives: Adults, Children (TrialNet) >20yrs . Universal Childhood Screening >20yrs • 15-19yrs HLA risk screening at birth followed by screening for multiple islet autoantibodies in 10-14yrs HLA at-risk cohort (TEDDY) <5yrs 15-19yrs 10-14yrs 5-9yrs 5-9yrs • Universal screening for multiple islet autoantibodies of population-based young children (FR1DA ) Diane K. Wherrett et al. Dia Care 2015;38:1975-1985 17 Many Type 1 Diabetes Preventions Variables Affecting Rate of Progression from Have Been Successul in NOD Mice Stage 1 to Stage 3 AAV murine IL-10 Gonadectomy AAV rat preproinsulin gene (vLP-1) Mycobacterium avium Guanidinoethyldisulphide Adenovirus expressing mIL-4 Mycobacterium leprae Heat shock protein 65 Aerosol insulin Natural antibodies Heat shock protein peptide (p277) Allogenic thymic macrophages Natural polyreactive autoantibodies Hematopoietic stem cells encoding proinsulin Alpha Galactosylceramide Neuropeptide calcitonin gene-related peptide Housing alone Alpha-interferon (rIFN-alpha) Nicotinamide Human IGF-1 Alpha/beta T cell receptor thymocytes Nicotine . Aminoguanidine I-A beta g7(54-76) peptide Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation Number of autoantibodies Anti-I-A monoclonal antibodies Androgens NKT cells Anti-ICAM-1 Anesthesia NY4.2 cells IgG2a antibodies Antioxidant MDL 29,311 OK432 Immobilization Antisense GAD mRNA Overcrowding Inomide Azathioprine Pancreatectomy Anti-integrin alpha 4 Anti-B7-1 Pentoxifylline Insulin (intraperitoneal, oral, subcutaneous, nasal) Bacille Calmette Gue’rin (BCG) Pertussigen Insulin B chain (plasmid) Baclofen Poly [I:C] Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal) Bee venom Pregestimil diet . Insulin-like growth factor I (IGF-I) Autoantibody specificities Biolistic-mediated IL-4 Prenatal stress Anti-intercellular adhesion molecule-1 (ICAM-1) Blocking peptide of MHC class II Preproinsulin DNA Bone marrow transplantation Interferon-alpha (oral) Probucol Interferon-gamma Castration Prolactin Anti-CD3 Anti-interferon-gamma Rampamycin Interferon-gamma receptor/IgG1 fusion protein Anti-CD4 Recombinant vaccinia virus expressing GAD CD4+CD25+regulatory T cells Interleukin-1 Reg protein Interleukin-4 Anti-CD8 Reg protein Anti-CD28 MAb Interleukin-4-Ig fusion protein Rolipram Interleukin-4-plasmid . Cholera toxin B subunit-insulin protein Saline (repeated injection) Autoantibody titer Interleukin-10 Class I derived self-I-A beta(g7) (54-76) peptide Schistosoma mansoni Interleukin-10-plasmid DNA Cold exposure Semi-purified diet (e.g., AIN-76) Interleukin-10-viral Anti-complement receptor Short term chronic stress Interleukin 11-human Complete Freund’s adjuvant Silica Anti-CTLA-4 Interleukin-12 Sirolimus/tacrolimus Intrathymic administration of mycobacterial heat shock protein 65 Cyclic nucleotide phosphodiesterases (PDEs) Sodium fusidate Cyclosporin Intrathymic administration of mycobacterial heat shock peptide p277 Soluble interferon-gamma receptor Islet cells-intrathymic Cyclosporin A Somatostatin DC deficient in NF-kappaB L-Selectin (MEL-14) Non-specific pathogen free conditions Lactate dehydogenase virus (LDH) . Age of autoantibody seroconversion (< 3yrs general DC from pancreatic lymph node Streptococcal enterotoxins Large multilamellar liposome DC with IL-4 Streptozotocin Lazaroid Deflazacort Sulfatide (3’sulfogalactosylceramide) Anti-leukocyte function associated antigen (LFA-1) Deoxysperogualin Superantigens Anti-LFA-1 Dexamethasone/progesterone/growth hormone/estradiol Superoxide dismutase-desferrioxamine Linomide (quinoline-3-carboxamide) Diazoxide Anti-T cell receptor Lipopolysaccharide-activated B cells population children; younger vs older relatives) 1,25 dihydroxy Vitamin D3, KH1060 TGF-beta 1 somatic gene therapy Lisofylline 1,25 dihydroxycholecalciferol Th1 clone specific for hsp60 peptide Lymphocyte choriomeningitis virus (LCMV) 1,25 dihydroxyl Vitamin D3 Anti-thy-1 Anti-lymphocyte serum Elevated temperature Thymectomy (neonatal) Lymphoctyte vaccination Emotionality Tolbutamide Encephalomyocarditis virus (ECMV) Lymphocytic choriomeningitis virus Tolerogenic dendritic cells induced by vitamin D receptor ligands Anti-L-selectin Essential fatty acid deficient diets Top of the rack FK506 Lymphotoxin Treatment combined with a 10% w/v sucrose-supplemented drinking water LZ8 FTY720 (myriocin) Tumor necrosis factor-alpha . GAD 65 peptides in utero MC1288 (20-epi-1,25-dihydroxyvitamin D3) TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) HLA (HLA DR3/DR4-DQ8), non-HLA genes MDL 29311 Anti-GAD monoclonal antibody Vitamin E Galactosylceramide Metabolically inactive insulin analog Anti-VLA-4 Glucose (neonatal) Anti-MHC class I Anti-MHC class II Glutamic acid decarboxylase MHC class II derived cyclic peptide (intraperitoneal, intrathymic, intravenous, oral) Glutamic acid decarboxylase 65 Th2 cell clone Mixed allogeneic chimerism Mixed bone marrow chimeras Glutamic acid decarboxylase peptides (intraperitoneal, intrathymic, intravenous, oral) Monosodium glutamate Murine hepatitis virus (MHV) May, 2016 15 Courtesy of Amanda Posgai and Mark Atkinson 3 8/14/2016 Human T1D Prevention Studies Have Had Very Limited Impact Other Studies in Recent-Onset T1D • DPT-1 Parenteral Insulin No effect Metabolic Control Study No effect • DPT-1 Oral Insulin No effect** DPP-4 Inhibitor + PPI No effect • TrialNet Oral Insulin Ongoing • ENDIT Nicotinamide No effect Pilot Studies: • DIPP Nasal Insulin No effect Low Dose IL-2 Safe • INIT-II Nasal Insulin Ongoing Plasmid-Encoded Proinsulin Safe • TRIGR Casein hydrolysate No effect on abs T-regs Safe • NIP Docosahexaenoic Acid No effect Dendritic Cells Safe • PRE-Point Oral Insulin Immunologic hints ** Post-hoc analysis identified subgroup with benefit Antigen-Based New Onset Use of Presymptomatic Stages of Type 1 Diabetes to Studies Design Type 1 Diabetes Prevention
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