Recessive mutations in IER3IP1 (Immediate Early Response 3 Interacting Protein 1) cause a triad of microcephaly, epilepsy, and permanent neonatal diabetes syndrome (MEDS) . IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development, however the role of IER3IP1 in β cell function and glucose homeostasis remains unknown. Herein, we established a new β cell-specific IER3IP1 knockout (IER3IP1-βKO) mouse model and found that IER3IP1 deficiency in β cells causes severe early onset insulin deficient diabetes. Functional studies revealed a markedly dilated ER along with significantly increased proinsulin misfolding and elevated expression of the ER chaperones including PDI, ERO1, BiP, and P58IPK. Transcriptome analysis confirmed by qRT-PCR revealed a markedly decreased expression of genes associated with β cell maturation, cell cycle, and anti-apoptosis, whereas there was a significantly increased expression of anti-proliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β cell maturation and proliferation, and promoted cell death. These data not only uncover a critical role of IER3IP1 in normal β cell function and survival, but they also provide insight into the mechanism (s) by which loss-of-function mutations of IER3IP1 lead to diabetes.


J.Yang: None. J.Sun: None. N.Li: None. T.Liu: None. S.Wang: None. X.Zhang: None. P.Arvan: n/a. M.Liu: None. J.Zhen: None. W.Feng: None. Z.Fan: None. Y.Huang: None. H.Shu: None. X.Li: None. J.Qiao: None. Y.Fan: None.


National Natural Science Foundation of China (81830025, 81620108004, 81870533, 81900720, 81800733, 82100865, 82070805, and 81870535)

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