| First Author | Yang J | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 45 | Pages | e2204443119 |
| PubMed ID | 36322741 | Mgi Jnum | J:336782 |
| Mgi Id | MGI:7435088 | Doi | 10.1073/pnas.2204443119 |
| Citation | Yang J, et al. (2022) IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of beta cells. Proc Natl Acad Sci U S A 119(45):e2204443119 |
| abstractText | 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 beta cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in beta cells, named IER3IP1-betaKO and IER3IP1-ibetaKO, respectively. We found that IER3IP1-betaKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated beta-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 beta-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-betaKO impaired beta-cell maturation and proliferation, along with increased condensation of beta-cell nuclear chromatin. Inducible beta-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 beta-cell early development. Importantly, IER3IP1 was decreased in beta cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with beta-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in beta cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations. |
