Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function

We used transgenesis to explore the requirement for downregulation of hepat ocyte nuclear factor 6 (HNF6) expression in the assembly, differentiation, and function of pancreatic islets, In vivo, HNF6 expression becomes downreg ulated in pancreatic endocrine cells at 18.5 days post coitum (d.p.c,), whe n definitive islets first begin to organize. We used an islet-specific regu latory element (pdx1(PB)) from pancreatic/duodenal homeobox (pdx1) gene to maintain HNF6 expression in endocrine cells beyond 18.5 d.p.c. Transgenic a nimals were diabetic. HNF6-overexpressing islets were hyperplastic and rema ined very close to the pancreatic ducts. Strikingly, alpha, delta, and PP c ells were increased in number and abnormally intermingled with islet beta c ells. Although several mature beta cell markers were expressed in beta cell s of transgenic Islets, the glucose transporter GLUT2 was absent or severel y reduced. As glucose uptake/metabolism is essential for insulin secretion, decreased GLUT2 may contribute to the etiology of diabetes in pdx1(PB)-HNF 6 transgenics. Concordantly, blood insulin was not raised by glucose challe nge, suggesting profound beta cell dysfunction. Thus, we have shown that HN F6 downregulation during islet ontogeny is critical to normal pancreas form ation and function: continued expression impairs the clustering of endocrin e cells and their separation from the ductal epithelium, disrupts the spati al organization of endocrine cell types within the islet, and severely comp romises beta cell physiology, leading to overt diabetes.