KEGG   PATHWAY: mmur04940
Entry
mmur04940                   Pathway                                
Name
Type I diabetes mellitus - Microcebus murinus (gray mouse lemur)
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
mmur04940  Type I diabetes mellitus
mmur04940

Organism
Microcebus murinus (gray mouse lemur) [GN:mmur]
Gene
105859822  INS; insulin [KO:K04526]
105881691  glutamate decarboxylase 1-like [KO:K01580] [EC:4.1.1.15]
105878118  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:4.1.1.15]
105880707  GAD1; glutamate decarboxylase 1 isoform X1 [KO:K01580] [EC:4.1.1.15]
105883238  PTPRN2; LOW QUALITY PROTEIN: receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:3.1.3.48]
105857665  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X3 [KO:K07817] [EC:3.1.3.48]
105874675  CPE; carboxypeptidase E [KO:K01294] [EC:3.4.17.10]
109729436  inactive carboxypeptidase-like protein X2 [KO:K01294] [EC:3.4.17.10]
105877936  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077] [EC:5.6.1.7]
105867264  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
105869751  SLA class II histocompatibility antigen, DQ haplotype C beta chain [KO:K06752]
105869752  HLA class II histocompatibility antigen, DQ alpha 2 chain [KO:K06752]
105869753  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
105876782  HLA class II histocompatibility antigen, DRB1-10 beta chain-like [KO:K06752]
105876793  mamu class II histocompatibility antigen, DR alpha chain isoform X1 [KO:K06752]
105886004  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
105886005  HLA class II histocompatibility antigen, DP beta 1 chain [KO:K06752]
105886009  HLA class II histocompatibility antigen, DP alpha 1 chain isoform X1 [KO:K06752]
105886010  HLA class II histocompatibility antigen, DM beta chain [KO:K06752]
105886015  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
105886026  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DQ beta 1 chain [KO:K06752]
105886027  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DO beta chain [KO:K06752]
105872012  HLA class II histocompatibility antigen, DRB1-1 beta chain-like [KO:K06752]
105879923  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
105879895  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
105856925  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
105881187  IL12A; interleukin-12 subunit alpha isoform X1 [KO:K05406]
105871571  IL12B; interleukin-12 subunit beta [KO:K05425]
105882081  IL2; interleukin-2 [KO:K05429]
105880942  IFNG; interferon gamma [KO:K04687]
105855949  HLA class I histocompatibility antigen, B-81 alpha chain-like [KO:K06751]
105855951  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, B-37 alpha chain-like [KO:K06751]
105870762  LOW QUALITY PROTEIN: saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
105870764  HLA class I histocompatibility antigen, B-37 alpha chain-like isoform X1 [KO:K06751]
105870765  HLA class I histocompatibility antigen, B-48 alpha chain-like [KO:K06751]
105870766  HLA class I histocompatibility antigen, B-44 alpha chain-like [KO:K06751]
105870767  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, alpha chain G-like [KO:K06751]
105858107  LOW QUALITY PROTEIN: class I histocompatibility antigen, Gogo-OKO alpha chain [KO:K06751]
105864623  uncharacterized protein LOC105864623 [KO:K10784]
105871667  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
105871657  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
105870191  PRF1; perforin-1 [KO:K07818]
105864427  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105864431  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105864432  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105864434  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105864436  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105864583  granzyme B-like [KO:K01353] [EC:3.4.21.79]
105858138  LTA; lymphotoxin-alpha [KO:K05468]
105858137  TNF; tumor necrosis factor isoform X1 [KO:K03156]
105859191  IL1A; interleukin-1 alpha isoform X1 [KO:K04383]
105859190  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
mmur04210  Apoptosis
mmur04660  T cell receptor signaling pathway
KO pathway
ko04940   
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