Background: Mutations in the gene for immediate early response 3 interacting protein 1 (IER3IP1) caused permanent neonatal diabetes in human. In previous report, we showed IER3IP1 KD induced cell death and decreased proliferation in MIN6 cells. In this study, we define the role of IER3IP1 in β-cells in vivo, and identify the mechanism of diabetes induced by IER3IP1 deficiency in mice.
Methods: In order to determine the role of IER3IP1 in β-cells and molecular mechanism by which IER3IP1 deficiency cause diabetes, IER3IP1 specific β-cell knockout mice lines were generated using RIP-Cre transgenic mice (βKO).
Results: There was no significant difference in the body weight between Βko mice and WT (IER3IP1+/+Cre+) mice. βKO mice develop glucose intolerance and decreased insulin secretion response to glucose in vivo as well as in isolated islets compared to WT mice. Moreover, βKO mice showed a decrease in β-cell mass due to the increase in β-cell death. Furthermore, deletion of IER3IP1 in β-cells causes ER stress. Both mRNA and protein levels of IRE1α were increased while spliced XBP1 (sXBP1), a downstream target of IRE1α, was decreased in the two animal models.
Conclusion: IER3IP1 deficiency in β-cells induces diabetes via disruption IRE1α-XBP1 signaling pathway.
L. Men: None. L. Qiao: None. J. Du: None. D. Ren: None.
