KEGG   PATHWAY: rno04940
Entry
rno04940                    Pathway                                
Name
Type I diabetes mellitus - Rattus norvegicus (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
rno04940  Type I diabetes mellitus
rno04940

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24379  Gad1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
24380  Gad2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
116660  Ptprn; receptor-type tyrosine-protein phosphatase-like N precursor [KO:K07817] [EC:3.1.3.48]
29714  Ptprn2; receptor-type tyrosine-protein phosphatase N2 precursor [KO:K07817] [EC:3.1.3.48]
25669  Cpe; carboxypeptidase E precursor [KO:K01294] [EC:3.4.17.10]
63868  Hspd1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
103694176  Hspd1l1; 60 kDa heat shock protein, mitochondrial-like [KO:K04077] [EC:5.6.1.7]
81024  Ica1; islet cell autoantigen 1 [KO:K19863]
294274  RT1-DMa; RT1 class II, DM alpha precursor [KO:K06752]
294273  RT1-DMb; RT1 class II, DM beta precursor [KO:K06752]
24984  RT1-DOa; RT1 class II, locus DOa precursor [KO:K06752]
24986  RT1-Ha; RT1 class II, locus Ha precursor [KO:K06752]
294269  RT1-Da; RT1 class II, locus Da precursor [KO:K06752]
294270  RT1-Db1; rano class II histocompatibility antigen, D-1 beta chain precursor [KO:K06752]
309621  RT1-Ba; rano class II histocompatibility antigen, B alpha chain precursor [KO:K06752]
309622  RT1-Bb; rano class II histocompatibility antigen, B-1 beta chain precursor [KO:K06752]
365542  RT1-DOb; RT1 class II, DO beta isoform 1 [KO:K06752]
24981  RT1-Db2; RT1 class II, locus Db2 precursor [KO:K06752]
25408  Cd80; T-lymphocyte activation antigen CD80 [KO:K05412]
56822  Cd86; T-lymphocyte activation antigen CD86 precursor [KO:K05413]
25660  Cd28; T-cell-specific surface glycoprotein CD28 precursor [KO:K06470]
84405  Il12a; interleukin-12 subunit alpha precursor [KO:K05406]
64546  Il12b; interleukin-12 subunit beta precursor [KO:K05425]
116562  Il2; interleukin-2 precursor [KO:K05429]
25712  Ifng; interferon gamma precursor [KO:K04687]
24747  RT1-M3-1; RT1 class Ib, locus M3-1 precursor [KO:K06751]
24750  RT1-N3; RT1 class Ib, locus N3 [KO:K06751]
24973  RT1-A1; RT1 class Ia, locus A1 precursor [KO:K06751]
24974  RT1-A2; RT1 class Ia, locus A2 precursor [KO:K06751]
24988  RT1-M2; RT1 class Ib, locus M2 precursor [KO:K06751]
294213  RT1-M1-4; RT1 class I, locus M1, gene 4 precursor [KO:K06751]
309600  RT1-CE12; RT1 class I, locus CE12 precursor [KO:K06751]
309603  RT1-CE1; RT1 class I, locus CE1 precursor [KO:K06751]
309607  RT1-CE5; RT1 class I, locus CE5 isoform 1 precursor [KO:K06751]
309627  RT1-A3; RT1 class I, locus A3 precursor [KO:K06751]
361787  RT1-T24-1; RT1 class I, locus T24, gene 1 isoform 1 [KO:K06751]
365527  RT1-M6-2; RT1 class I, locus M6, gene 2 precursor [KO:K06751]
368153  RT1-CE7; RT1 class I, locus CE7 precursor [KO:K06751]
414779  RT1-CE2; RT1 class I, locus CE2 precursor [KO:K06751]
414783  RT1-CE4; RT1 class I, locus CE4 precursor [KO:K06751]
414784  RT1-T24-4; RT1 class I, locus T24, gene 4 [KO:K06751]
414785  RT1-M6-1; RT1 class I, locus M6, gene 1 precursor [KO:K06751]
414786  RT1-M1-2; RT1 class I, locus M1, gene 2 precursor [KO:K06751]
414789  RT1-CE15; RT1 class I, locus CE15 precursor [KO:K06751]
414790  RT1-CE13; RT1 class I, locus CE13 precursor [KO:K06751]
414791  RT1-CE11; RT1 class I, locus CE11 precursor [KO:K06751]
414792  RT1-CE10; RT1 class I, locus CE10 precursor [KO:K06751]
414793  RT1-CE3; RT1 class I, locus CE3 precursor [KO:K06751]
414819  RT1-CE16; RT1 class I, locus CE16 precursor [KO:K06751]
24751  RT1-O1; RT1 class Ib, locus O1 [KO:K06751]
406194  RT1-T18; RT1 class Ib, locus T18 precursor [KO:K06751]
294228  RT1-S3; RT1 class Ib, locus S3 precursor [KO:K06751]
309584  RT1-M4; RT1 class Ib, locus M4 precursor [KO:K06751]
360323  RT1-N2; RT1 class Ib, locus N2 precursor [KO:K06751]
414788  RT1-T24-3; RT1 class I, locus T24, gene 3 [KO:K06751]
680842  RT1-M1-5; RT1 class I, M1, gene 5 precursor [KO:K06751]
102546590  H2-M10.6l; patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
499400  RT1-M5; RT1 class Ib, locus M5 isoform 2 precursor [KO:K06751]
25385  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
50669  Prf1; perforin-1 precursor [KO:K07818]
171528  Gzmb; granzyme B precursor [KO:K01353] [EC:3.4.21.79]
25008  Lta; lymphotoxin-alpha precursor [KO:K05468]
24835  Tnf; tumor necrosis factor [KO:K03156]
24493  Il1a; interleukin-1 alpha [KO:K04383]
24494  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
rno04210  Apoptosis
rno04660  T cell receptor signaling pathway
KO pathway
ko04940   

  All links  
Genome (1)   
   KEGG GENOME (1)   
Gene (68)   
   KEGG GENES (68)   
All databases (69)   

Download RDF
DBGET integrated database retrieval system