GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice

Deficiencies in pancreatic beta-cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein (GRP) 94, an endoplasmic reticulum protein abundantly expressed in the pancreatic acini and islets, in beta-cell development, survival, and function. We used a conditional knockout (KO) mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. These Hsp90b1 (flox/flox); Pdx1(Cre) KO mice exhibited pancreatic hypoplasia at embryonic day (E) 16.5 to E18.5 and had significantly reduced beta-cell mass at 4 weeks after birth. Further mechanistic studies showed that deletion of GRP94 reduced beta-cell proliferation with increased cell apoptosis in both Pdx1(+) endocrine progenitor cells and differentiated beta cells. Although Hsp90b1 (flox/flox); Pdx1(Cre) KO mice remained euglycemic at 8 weeks of age, they exhibited impaired glucose tolerance. In aggregate, these findings indicate that GRP94 is an essential regulator of pancreatic beta-cell development, mass, and function.