Immune-mediated beta-cell destruction in vitro and in vivo-A pivotal role for galectin-3.
Pro-apoptotic cytokines are toxic to the pancreatic beta-cells and have been associated with the pathogenesis of Type 1 diabetes (T1D). Proteome analysis of IL-1beta exposed isolated rat islets identified galectin-3 (gal-3) as the most up-regulated protein. Here analysis of human and rat islets and insulinoma cells confirmed IL-1beta regulated gal-3 expression of several gal-3 isoforms and a complex in vivo expression profile during diabetes development in rats. Over-expression of gal-3 protected beta-cells against IL-1beta toxicity, with a complete blockage of JNK phosphorylation, essential for IL-1-mediated apoptosis. Mutation scanning of regulatory and coding regions of the gal-3 gene (LGALS3) identified six polymorphisms. A haplotype comprising three cSNPs showed significantly increased transmission to unaffected offspring in 257 T1D families and replicated in an independent set of 170 T1D families. In summary, combined proteome-transcriptome-genome and functional analyses identify gal-3 as a candidate gene/protein in T1D susceptibility that may prove valuable in future intervention/prevention strategies.
Karlsen
Allan E
AE
Steno Diabetes Center, Gentofte, Denmark. aek@novonordisk.com
Størling
Zenia M
ZM
Sparre
Thomas
T
Larsen
Martin R
MR
Mahmood
Amer
A
Størling
Joachim
J
Roepstorff
Peter
P
Wrzesinski
Krzysztof
K
Larsen
Peter Mose
PM
Fey
Stephen
S
Nielsen
Karin
K
Heding
Peter
P
Ricordi
Camillo
C
Johannesen
Jesper
J
Kristiansen
Ole P
OP
Christensen
Ulla B
UB
Kockum
Ingrid
I
Luthman
Holger
H
Nerup
Jørn
J
Pociot
Flemming
F
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000633:toxicity*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology*; D007375:Interleukin-1 / Q000633:toxicity; D009154:Mutation; D010770:Phosphotransferases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D016207:Cytokines; D037502:Galectin 3; D007375:Interleukin-1; D012333:RNA, Messenger; D010770:Phosphotransferases