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Endocrinology. 2018 Feb 1;159(2):1062-1073. doi: 10.1210/en.2017-00685.

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

Author information

1
Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
2
Department of Medicine, Tulane University, New Orleans, Louisiana.
3
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
4
Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina.
5
Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.

Abstract

Deficiencies in pancreatic β-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 β-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;Pdx1Cre KO mice exhibited pancreatic hypoplasia at embryonic day (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 Hsp90b1 flox/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.

PMID:
29272356
PMCID:
PMC5793778
[Available on 2019-02-01]
DOI:
10.1210/en.2017-00685
[Indexed for MEDLINE]

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