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Acute Deletion of METTL14 in ?-Cells of Adult Mice Results in Glucose Intolerance.


ABSTRACT: N6-Methyladenosine (m6A) is the most common and abundant mRNA modification that involves regulating the RNA metabolism. However, the role of m6A in regulating the ?-cell function is unclear. Methyltransferase-like 14 (METTL14) is a key component of the m6A methyltransferase complex. To define the role of m6A in regulating the ?-cell function, we generated ?-cell METTL14-specific knockout (?KO) mice by tamoxifen administration. Acute deletion of Mettl14 in ?-cells results in glucose intolerance as a result of a reduction in insulin secretion in ?-cells even though ?-cell mass is increased, which is related to increased ?-cell proliferation. To define the molecular mechanism, we performed RNA sequencing to detect the gene expression in ?KO islets. The genes responsible for endoplasmic reticulum stress, such as Ire1?, were among the top upregulated genes. Both mRNA and protein levels of IRE1? and spliced X-box protein binding 1 (sXBP-1) were increased in ?KO islets. The protein levels of proinsulin and insulin were decreased in ?KO islets. These results suggest that acute METTL14 deficiency in ?-cells induces glucose intolerance by increasing the IRE1?/sXBP-1 pathway.

SUBMITTER: Men L 

PROVIDER: S-EPMC6760293 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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