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

Kim DS, Song L, Wang J, Wu H, Gu G, Sugi Y, Li Z, Wang H
Endocrinology. 2018 159 (2): 1062-1073

PMID: 29272356 · PMCID: PMC5793778 · DOI:10.1210/en.2017-00685

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.

Copyright © 2018 Endocrine Society.

MeSH Terms (17)

Animals Cell Count Cell Differentiation Cell Proliferation Cells, Cultured Embryo, Nonmammalian Glucose Intolerance HEK293 Cells Humans Insulin-Secreting Cells Male Membrane Glycoproteins Mice Mice, Inbred C57BL Mice, Knockout Organ Size Pancreas

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