KEGG   PATHWAY: uah04940
uah04940                    Pathway                                

Type I diabetes mellitus - Ursus arctos horribilis
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.
Human Diseases; Endocrine and metabolic disease
Pathway map
uah04940  Type I diabetes mellitus

Ursus arctos horribilis [GN:uah]
113243960  insulin-like [KO:K04526]
113253470  glutamate decarboxylase 1-like [KO:K01580] [EC:]
113241322  GAD2; glutamate decarboxylase 2 [KO:K01580] [EC:]
113250787  GAD1; glutamate decarboxylase 1 [KO:K01580] [EC:]
113250429  PTPRN; receptor-type tyrosine-protein phosphatase-like N isoform X1 [KO:K07817] [EC:]
113241529  PTPRN2; receptor-type tyrosine-protein phosphatase N2 [KO:K07817] [EC:]
113255825  CPE; carboxypeptidase E isoform X1 [KO:K01294] [EC:]
113250626  HSPD1; 60 kDa heat shock protein, mitochondrial [KO:K04077]
113260534  ICA1; islet cell autoantigen 1 isoform X1 [KO:K19863]
113243684  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP alpha 1 chain-like [KO:K06752]
113243685  LOW QUALITY PROTEIN: HLA class II histocompatibility antigen, DP beta 1 chain-like [KO:K06752]
113243774  HLA class II histocompatibility antigen, DR alpha chain [KO:K06752]
113243775  DLA class II histocompatibility antigen, DR-1 beta chain [KO:K06752]
113243776  SLA class II histocompatibility antigen, DQ haplotype D alpha chain-like [KO:K06752]
113243777  HLA class II histocompatibility antigen, DQ beta 1 chain-like [KO:K06752]
113243778  DLA class II histocompatibility antigen, DR-1 beta chain-like [KO:K06752]
113243779  HLA class II histocompatibility antigen, DO beta chain isoform X1 [KO:K06752]
113243784  HLA class II histocompatibility antigen, DM beta chain isoform X1 [KO:K06752]
113243786  HLA class II histocompatibility antigen, DM alpha chain isoform X1 [KO:K06752]
113243788  HLA class II histocompatibility antigen, DO alpha chain [KO:K06752]
113251861  CD80; T-lymphocyte activation antigen CD80 [KO:K05412]
113252170  CD86; T-lymphocyte activation antigen CD86 isoform X1 [KO:K05413]
113250560  CD28; T-cell-specific surface glycoprotein CD28 [KO:K06470]
113254130  IL12A; interleukin-12 subunit alpha [KO:K05406]
113263879  IL12B; interleukin-12 subunit beta [KO:K05425]
113255635  IL2; interleukin-2 [KO:K05429]
113256304  IFNG; interferon gamma [KO:K04687]
113249452  HLA class I histocompatibility antigen, A-11 alpha chain-like isoform X1 [KO:K06751]
113250163  saoe class I histocompatibility antigen, A alpha chain-like [KO:K06751]
113264228  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, A-3 alpha chain [KO:K06751]
113243704  DLA class I histocompatibility antigen, A9/A9 alpha chain-like isoform X1 [KO:K06751]
113243706  HLA class I histocompatibility antigen, alpha chain G-like isoform X1 [KO:K06751]
113243878  LOW QUALITY PROTEIN: HLA class I histocompatibility antigen, A-32 alpha chain-like [KO:K06751]
113261534  H-2 class I histocompatibility antigen, Q10 alpha chain-like [KO:K06751]
113265359  uncharacterized protein LOC113265359 [KO:K10785]
113262825  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
113258968  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
113259145  PRF1; perforin-1 [KO:K07818]
113245994  granzyme B-like isoform X1 [KO:K01353] [EC:]
113243662  LTA; lymphotoxin-alpha [KO:K05468]
113243711  TNF; tumor necrosis factor [KO:K03156]
113268160  IL1A; interleukin-1 alpha [KO:K04383]
113242506  IL1B; interleukin-1 beta [KO:K04519]
C00027  Hydrogen peroxide
C00533  Nitric oxide
C00704  Superoxide
Rabinovitch A, Suarez-Pinzon WL.
Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus.
Biochem Pharmacol 55:1139-49 (1998)
Cox NJ, Wapelhorst B, Morrison VA, Johnson L, Pinchuk L, Spielman RS, Todd JA, Concannon P
Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families.
Am J Hum Genet 69:820-30 (2001)
Davies JL, Kawaguchi Y, Bennett ST, Copeman JB, Cordell HJ, Pritchard LE, Reed PW, Gough SC, Jenkins SC, Palmer SM, et al.
A genome-wide search for human type 1 diabetes susceptibility genes.
Nature 371:130-6 (1994)
Fujisawa T, Ikegami H, Kawaguchi Y, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Shima K, Ogihara T.
Class I HLA is associated with age-at-onset of IDDM, while class II HLA confers susceptibility to IDDM.
Diabetologia 38:1493-5 (1995)
Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H.
Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase.
J Exp Med 197:1635-44 (2003)
Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, Yu L, Wegmann DR, Hutton JC, Elliott JF, Eisenbarth GS.
Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice.
Nature 435:220-3 (2005)
Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA.
Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope.
Nature 435:224-8 (2005)
Lieberman SM, DiLorenzo TP.
A comprehensive guide to antibody and T-cell responses in type 1 diabetes.
Tissue Antigens 62:359-77 (2003)
Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC.
Granzyme B: a natural born killer.
Immunol Rev 193:31-8 (2003)
uah04210  Apoptosis
uah04660  T cell receptor signaling pathway
KO pathway

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