Immune-mediated β-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 I diabetes (T1D). Proteome analysis of IL-1 beta 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-1 beta 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-1 beta 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-genorne and functional analyses identify gal-3 as a candidate gene/protein in T1D susceptibility that may prove valuable in future intervention/prevention strategies. (c) 2006 Elsevier Inc. All rights reserved.