KEGG   PATHWAY: morg04940
Entry
morg04940                   Pathway                                
Name
Type I diabetes mellitus - Microtus oregoni (creeping vole)
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
morg04940  Type I diabetes mellitus
morg04940

Organism
Microtus oregoni (creeping vole) [GN:morg]
Gene
121457317  Ins; insulin [KO:K04526]
121433227  Gad1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
121440739  Gad2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
121438447  Ptprn2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
121447134  Ptprn; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
121462808  Cpe; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
121455698  60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
121458720  Hspd1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
121456790  60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
121440146  60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
121463355  Ica1; islet cell autoantigen 1 isoform X1 [KO:K19863]
121435294  rano class II histocompatibility antigen, A beta chain-like [KO:K06752]
121435295  H-2 class II histocompatibility antigen, A beta chain-like [KO:K06752]
121435296  H-2 class II histocompatibility antigen, E-S beta chain-like [KO:K06752]
121435298  class II histocompatibility antigen, M beta 1 chain [KO:K06752]
121435299  class II histocompatibility antigen, M alpha chain [KO:K06752]
121435301  HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
121435302  H-2 class II histocompatibility antigen, I-E alpha chain-like [KO:K06752]
121435303  H-2 class II histocompatibility antigen, A-F alpha chain-like [KO:K06752]
121435304  RLA class II histocompatibility antigen, DP alpha-1 chain isoform X1 [KO:K06752]
121435309  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
121435311  H-2 class II histocompatibility antigen, E-S beta chain-like isoform X1 [KO:K06752]
121435709  HLA class II histocompatibility antigen, DR beta 5 chain-like [KO:K06752]
121435710  H-2 class II histocompatibility antigen, E-U alpha chain [KO:K06752]
121435711  HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
121461624  Cd80; T-lymphocyte activation antigen CD80 [KO:K05412]
121462063  Cd86; T-lymphocyte activation antigen CD86 [KO:K05413]
121452787  Cd28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
121452968  Il12a; interleukin-12 subunit alpha [KO:K05406]
121464009  Il12b; interleukin-12 subunit beta [KO:K05425]
121452714  Il2; interleukin-2 [KO:K05429]
121456003  Ifng; interferon gamma [KO:K04687]
121435269  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435270  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435271  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435272  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435273  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435274  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435275  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435277  RT1 class I histocompatibility antigen, AA alpha chain-like isoform X1 [KO:K06751]
121435283  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435313  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
121435364  class I histocompatibility antigen, Non-RT1.A alpha-1 chain-like isoform X1 [KO:K06751]
121435376  class I histocompatibility antigen, Non-RT1.A alpha-1 chain-like isoform X1 [KO:K06751]
121435377  H-2 class I histocompatibility antigen, Q10 alpha chain-like isoform X1 [KO:K06751]
121435378  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
121435379  H-2 class I histocompatibility antigen, D-37 alpha chain-like [KO:K06751]
121435380  H-2 class I histocompatibility antigen, L-D alpha chain-like [KO:K06751]
121435381  H-2 class I histocompatibility antigen, L-D alpha chain-like isoform X1 [KO:K06751]
121435382  H-2 class I histocompatibility antigen, D-37 alpha chain-like isoform X1 [KO:K06751]
121435464  class I histocompatibility antigen, B alpha chain-like [KO:K06751]
121435500  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
121435594  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
121435668  class I histocompatibility antigen, Gogo-B*0103 alpha chain-like [KO:K06751]
121435669  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
121435693  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
121435695  putative HLA class I histocompatibility antigen, alpha chain H [KO:K06751]
121435698  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
121455415  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
121454281  Fas; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
121450939  Prf1; perforin-1 [KO:K07818]
121435007  granzyme C-like [KO:K01353] [EC:3.4.21.79]
121435008  granzyme B-like [KO:K01353] [EC:3.4.21.79]
121435012  granzyme B(G,H)-like isoform X1 [KO:K01353] [EC:3.4.21.79]
121435321  Lta; lymphotoxin-alpha [KO:K05468]
121435312  Tnf; tumor necrosis factor isoform X1 [KO:K03156]
121460451  Il1a; interleukin-1 alpha [KO:K04383]
121460531  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
PMID:11507694
  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
PMID:12796471
  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
PMID:15889095
  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
PMID:15889096
  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
PMID:14617043
  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
PMID:12752668
  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
morg04210  Apoptosis
morg04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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