METTL14 is essential for β-cell survival and insulin secretion.

Defects in the development, maintenance or expansion of β-cell mass can result in impaired glucose metabolism and diabetes. N6-methyladenosine affects mRNA stability and translation efficiency, and impacts cell differentiation and stress response. To determine if there is a role for m6A in β-cells, we investigated the effect of Mettl14, a key component of the m6A methyltransferase complex, on β-cell survival and function using rat insulin-2 promoter-Cre-mediated deletion of Mettl14 mouse line (βKO). We found that βKO mice with normal chow exhibited glucose intolerance, lower levels of glucose-stimulated insulin secretion, increased β-cell death and decreased β-cell mass. In addition, HFD-fed βKO mice developed glucose intolerance, decreased β-cell mass and proliferation, exhibited lower body weight, increased adipose tissue mass, and enhanced insulin sensitivity due to enhanced AKT signaling and decreased gluconeogenesis in the liver. HFD-fed βKO mice also showed a decrease in de novo lipogenesis, and an increase in lipolysis in the liver. RNA sequencing in islets revealed that Mettl14 deficiency in β-cells altered mRNA expression levels of some genes related to cell death and inflammation. Together, we showed that Mettl14 in β-cells plays a key role in β-cell survival, insulin secretion and glucose homeostasis.