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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Count
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Embryo, Nonmammalian
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • HEK293 Cells
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / physiology*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size / genetics
  • Pancreas / embryology*
  • Pancreas / growth & development
  • Pancreas / physiology

Substances

  • Membrane Glycoproteins
  • endoplasmin