KEGG   PATHWAY: mun04940
Entry
mun04940                    Pathway                                
Name
Type I diabetes mellitus - Meriones unguiculatus (Mongolian gerbil)
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
mun04940  Type I diabetes mellitus
mun04940

Organism
Meriones unguiculatus (Mongolian gerbil) [GN:mun]
Gene
110547298  Ins; insulin [KO:K04526]
110549838  Gad1; glutamate decarboxylase 1 [KO:K01580] [EC:4.1.1.15]
110565931  Gad2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
110539330  Ptprn; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:3.1.3.48]
110551806  Ptprn2; receptor-type tyrosine-protein phosphatase N2 isoform X1 [KO:K07817] [EC:3.1.3.48]
110549041  Cpe; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
110551641  Hspd1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
110551573  Ica1; islet cell autoantigen 1 isoform X1 [KO:K19863]
110543060  class II histocompatibility antigen, M alpha chain [KO:K06752]
110543088  class II histocompatibility antigen, M beta 1 chain isoform X1 [KO:K06752]
110543117  H-2 class II histocompatibility antigen, E-D beta chain-like isoform X1 [KO:K06752]
110543181  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
110543223  H-2 class II histocompatibility antigen, I-E beta chain-like [KO:K06752]
110543234  rano class II histocompatibility antigen, B-1 beta chain-like [KO:K06752]
110543301  HLA class II histocompatibility antigen, DP beta 1 chain-like isoform X2 [KO:K06752]
110543331  RLA class II histocompatibility antigen, DP alpha-1 chain isoform X1 [KO:K06752]
110544088  H-2 class II histocompatibility antigen, A-F alpha chain [KO:K06752]
110542965  HLA class II histocompatibility antigen, DO beta chain isoform X2 [KO:K06752]
110543034  H-2 class II histocompatibility antigen, E-U alpha chain-like [KO:K06752]
110555398  Cd80; T-lymphocyte activation antigen CD80 isoform X1 [KO:K05412]
110540129  Cd86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
110554770  Cd28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
110557307  Il12a; interleukin-12 subunit alpha [KO:K05406]
110548438  Il12b; interleukin-12 subunit beta [KO:K05425]
110545874  Il2; interleukin-2 [KO:K05429]
110560079  interleukin-2-like [KO:K05429]
110561827  Ifng; interferon gamma [KO:K04687]
110557144  H-2 class I histocompatibility antigen, D-37 alpha chain-like [KO:K06751]
110557146  RT1 class I histocompatibility antigen, AA alpha chain-like isoform X1 [KO:K06751]
110562341  BOLA class I histocompatibility antigen, alpha chain BL3-7-like isoform X3 [KO:K06751]
110563045  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
110563046  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
110563052  class I histocompatibility antigen, B alpha chain-like [KO:K06751]
110543171  H-2 class I histocompatibility antigen, K-D alpha chain-like [KO:K06751]
110543428  RT1 class I histocompatibility antigen, AA alpha chain-like isoform X1 [KO:K06751]
110544579  patr class I histocompatibility antigen, A-126 alpha chain-like [KO:K06751]
132648276  patr class I histocompatibility antigen, A-2 alpha chain-like [KO:K06751]
110543095  RT1 class I histocompatibility antigen, AA alpha chain-like isoform X1 [KO:K06751]
110557135  RT1 class I histocompatibility antigen, AA alpha chain [KO:K06751]
132648299  RT1 class I histocompatibility antigen, AA alpha chain-like isoform X1 [KO:K06751]
110556827  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
110561521  Fas; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
110555907  Prf1; perforin-1 [KO:K07818]
110559569  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
110559571  granzyme B(G,H)-like [KO:K01353] [EC:3.4.21.79]
110565882  granzyme C-like [KO:K01353] [EC:3.4.21.79]
110560136  Tnf; LOW QUALITY PROTEIN: tumor necrosis factor [KO:K03156]
110551396  Il1a; interleukin-1 alpha [KO:K04383]
110551400  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
mun04210  Apoptosis
mun04660  T cell receptor signaling pathway
KO pathway
ko04940   
LinkDB

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