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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,11,8]]},"abstract":"<jats:p>Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in \u03b2 cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in \u03b2 cells, named IER3IP1-\u03b2KO and IER3IP1-i\u03b2KO, respectively. We found that IER3IP1-\u03b2KO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated \u03b2-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with \u03b2-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-\u03b2KO impaired \u03b2-cell maturation and proliferation, along with increased condensation of \u03b2-cell nuclear chromatin. Inducible \u03b2-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after \u03b2-cell early development. Importantly, IER3IP1 was decreased in \u03b2 cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with \u03b2-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in \u03b2 cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.<\/jats:p>","DOI":"10.1073\/pnas.2204443119","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T14:50:06Z","timestamp":1667400606000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of \u03b2 cells"],"prefix":"10.1073","volume":"119","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Zhen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, 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