Perspectives in Diabetes A Genetic Switch in Pancreatic -Cells Implications for Differentiation and Haploinsufficiency

Heterozygous mutations in the genes encoding tran-scriptional regulators hepatocyte nuclear factor (HNF)-1 and HNF-4 cause a form of diabetes known as maturity-onset diabetes of the young (MODY). Haploin-sufficiency of HNF-1 or HNF-4 results in MODY be-cause of defective function of pancreatic islet cells. In contrast, homozygous null mutations in mouse models lead to widespread and profound gene expression de-fects in multiple cell types. Thus, it is not surprising that HNF-1 function is now known to have distinct properties in pancreatic -cells. It controls a complex tissue-selective genetic network that is activated when pancreatic cells differentiate, and allows these cells to maintain critical specialized functions. The network contains an indispensable core component formed by