IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic beta cells

In mammalian pancreatic beta cells, the IRE1 alpha-XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed beta cell-specific Ire1 alpha conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1 alpha was deleted using the Cre-loxP system. Ire1a CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4-20 weeks. Ire1a deletion in pancreatic beta cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1 alpha-XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1 alpha functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic beta cells.