GRP94 is an Essential Regulator of Pancreatic β Cell Development, Mass and Function in Male Mice.
- PMID: 29272356 [PubMed].
Deficiencies in pancreatic β cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein 94 (GRP94), an endoplasmic reticulum (ER) protein abundantly expressed in the pancreatic acini and islets, in β cell development, survival, and function. We used a conditional knockout mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in Pdx1 (pancreatic and duodenal homeobox 1) expressing cells. These Hsp90b1flox/flox;Pdx1Cre KO mice exhibited pancreatic hypoplasia at embryonic days (E) 16.5 to E18.5, and had significantly reduced β cell mass at 4 weeks after birth. Further mechanistic studies showed that deletion of GRP94 reduced β cell proliferation with increased cell apoptosis in both Pdx1+ endocrine progenitor cells, and differentiated β cells. Although Hsp90b1flox/flox;Pdx1Cre 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 β cell development, mass, and function.