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

Endocrinology
Lili MenDecheng Ren

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 β-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 β-cell function, we generated β-cell METTL14-specific knockout (βKO) mice by tamoxifen administration. Acute deletion of Mettl14 in β-cells results in glucose intolerance as a result of a reduction in insulin secretion in β-cells even though β-cell mass is increased, which is related to increased β-cell proliferation. To define the molecular mechanism, we performed RNA sequencing to detect the gene expression in βKO islets. The genes responsible for endoplasmic reticulum stress, such as Ire1α, were among the top upregulated genes. Both mRNA and protein levels of IRE1α and spliced X-box protein binding 1 (sXBP-1) were increased in βKO islets. The protein levels of proinsulin and insulin were decreased in βKO islets. These results suggest that acute METTL14 deficiency in β-cells induces glucose intolerance by increasing the IRE1α/sXBP-1 pathway.

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Citations

Aug 14, 2020·The Journal of Biological Chemistry·Rohit B SharmaLaura C Alonso
Jan 13, 2021·Cell & Bioscience·Jianzhong GuXinbing Sui
May 13, 2021·Journal of Diabetes Investigation·Mingli Sun, Xinan Zhang

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