Genome-wide association studies identified noncoding SNPs associated with type 2 
diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE 
and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; 
Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. 
(2007) Science 316:889-894]. We show that these LD blocks contain highly 
conserved noncoding elements and overlap with the genomic regulatory blocks of 
the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly 
conserved noncoding elements in LD with the risk SNPs drive expression in 
endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have 
recently been implicated in pancreas development and the regulation of insulin 
secretion, but IRX3 had no prior association with pancreatic function or 
development. Knockdown of its orthologue in zebrafish, irx3a, increased the 
number of pancreatic ghrelin-producing epsilon cells and decreased the number of 
insulin-producing beta-cells and glucagon-producing alpha-cells, thereby 
suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 
diabetes.