KEGG   PATHWAY: dord04940
Entry
dord04940                   Pathway                                
Name
Type I diabetes mellitus - Dipodomys ordii (Ord's kangaroo rat)
Description
Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma).
Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene.
Class
Human Diseases; Endocrine and metabolic disease
Pathway map
dord04940  Type I diabetes mellitus
dord04940

Organism
Dipodomys ordii (Ord's kangaroo rat) [GN:dord]
Gene
105989171  Ins; insulin [KO:K04526]
105994346  Gad1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
105984452  Gad2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
105993223  Ptprn; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
105991112  Cpe; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
105980195  Hspd1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
105988308  Ica1; islet cell autoantigen 1 isoform X1 [KO:K19863]
106002959  HLA class II histocompatibility antigen, DRB1-11 beta chain-like [KO:K06752]
105999831  HLA class II histocompatibility antigen, DM alpha chain [KO:K06752]
105999834  HLA class II histocompatibility antigen, DR beta 4 chain-like isoform X1 [KO:K06752]
105999835  HLA class II histocompatibility antigen, DRB1-12 beta chain-like [KO:K06752]
105999836  H-2 class II histocompatibility antigen, E-S beta chain-like isoform X1 [KO:K06752]
105999837  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
105999872  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
105999877  HLA class II histocompatibility antigen, DP beta 1 chain isoform X1 [KO:K06752]
105999881  HLA class II histocompatibility antigen, DP alpha 1 chain [KO:K06752]
105999888  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
105999890  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
106001844  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
105987998  Cd80; T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
105988000  Cd86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
105981051  Cd28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
105985549  Il12a; interleukin-12 subunit alpha [KO:K05406]
106001299  Il12b; interleukin-12 subunit beta [KO:K05425]
105989886  Il2; interleukin-2 [KO:K05429]
105988764  Ifng; interferon gamma [KO:K04687]
105996874  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
105996957  HLA class I histocompatibility antigen, B-7 alpha chain-like isoform X1 [KO:K06751]
105996958  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, B-27 alpha chain-like [KO:K06751]
105996964  HLA class I histocompatibility antigen, A-11 alpha chain-like [KO:K06751]
105996972  HLA class I histocompatibility antigen, B-46 alpha chain-like [KO:K06751]
106001400  LOW QUALITY PROTEIN: class I histocompatibility antigen, Non-RT1.A alpha-1 chain-like [KO:K06751]
106001802  H-2 class I histocompatibility antigen, Q9 alpha chain-like [KO:K06751]
106000422  uncharacterized protein LOC106000422 [KO:K10784]
105985196  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
105986214  Fas; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
105986283  Prf1; perforin-1 [KO:K07818]
105992458  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105992478  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105992489  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105997012  Lta; lymphotoxin-alpha [KO:K05468]
105997009  Tnf; tumor necrosis factor isoform X1 [KO:K03156]
105988223  Il1a; interleukin-1 alpha [KO:K04383]
105988300  Il1b; interleukin-1 beta [KO:K04519]
Compound
C00027  Hydrogen peroxide
C00533  Nitric oxide
C00704  Superoxide
Reference
PMID:9719467
  Authors
Rabinovitch A, Suarez-Pinzon WL.
  Title
Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus.
  Journal
Biochem Pharmacol 55:1139-49 (1998)
DOI:10.1016/S0006-2952(97)00492-9
Reference
  Authors
Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P
  Title
Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.
  Journal
Am J Hum Genet 69:820-30 (2001)
DOI:10.1086/323501
Reference
PMID:8072542
  Authors
Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al.
  Title
A genome-wide search for human type 1 diabetes susceptibility genes.
  Journal
Nature 371:130-6 (1994)
DOI:10.1038/371130a0
Reference
PMID:8786033
  Authors
Fujisawa T, Ikegami H, Kawaguchi Y, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Shima K, Ogihara T.
  Title
Class I HLA is associated with age-at-onset of IDDM, while class II HLA confers susceptibility to IDDM.
  Journal
Diabetologia 38:1493-5 (1995)
DOI:10.1007/BF00400620
Reference
  Authors
Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H.
  Title
Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.
  Journal
J Exp Med 197:1635-44 (2003)
DOI:10.1084/jem.20030215
Reference
  Authors
Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS.
  Title
Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.
  Journal
Nature 435:220-3 (2005)
DOI:10.1038/nature03523
Reference
  Authors
Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA.
  Title
Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.
  Journal
Nature 435:224-8 (2005)
DOI:10.1038/nature03625
Reference
  Authors
Lieberman SM, DiLorenzo TP.
  Title
A comprehensive guide to antibody and T-cell responses in type 1 diabetes.
  Journal
Tissue Antigens 62:359-77 (2003)
DOI:10.1034/j.1399-0039.2003.00152.x
Reference
  Authors
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
  Title
Granzyme B: a natural born killer.
  Journal
Immunol Rev 193:31-8 (2003)
DOI:10.1034/j.1600-065X.2003.00044.x
Related
pathway
dord04210  Apoptosis
dord04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

DBGET integrated database retrieval system