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

N6-Methyladenosine (m(6)A) is the most common and abundant mRNA modification that involves regulating the RNA metabolism. However, the role of m(6)A in regulating the beta-cell function is unclear. Methyltransferase-like 14 (METTL14) is a key component of the m(6)A methyltransferase complex. To define the role of m(6)A in regulating the beta-cell function, we generated beta-cell METTL14-specific knockout (beta KO) mice by tamoxifen administration. Acute deletion of Mettl14 in beta-cells results in glucose intolerance as a result of a reduction in insulin secretion in beta-cells even though beta-cell mass is increased, which is related to increased beta-cell proliferation. To define the molecular mechanism, we performed RNA sequencing to detect the gene expression in beta KO islets. The genes responsible for endoplasmic reticulum stress, such as Ire1 alpha, were among the top upregulated genes. Both mRNA and protein levels of IRE1 alpha and spliced X-box protein binding 1 (sXBP-1) were increased in beta KO islets. The protein levels of proinsulin and insulin were decreased in beta KO islets. These results suggest that acute METTL14 deficiency in beta-cells induces glucose intolerance by increasing the IRE1 alpha/sXBP-1 pathway.