Glucose Regulates m6A Methylation of RNA in Pancreatic Islets

Abstract

Type 2 diabetes is characterized by chronic hyperglycemia associated with impaired insulin action and secretion. Although the heritability of type 2 diabetes is high, the environment, including blood components, could play a major role in the development of the disease. Amongst environmental effects, epitranscriptomic modifications have been recently shown to affect gene expression and glucose homeostasis. The epitranscriptome is characterized by reversible chemical changes in RNA, with one of the most prevalent being the m6A methylation of RNA. Since pancreatic β cells fine tune glucose levels and play a major role in type 2 diabetes physiopathology, we hypothesized that the environment, through variations in blood glucose or blood free fatty acid concentrations, could induce changes in m6A methylation of RNAs in pancreatic β cells. Here we observe a significant decrease in m6A methylation upon high glucose concentration, both in mice and human islets, associated with altered expression levels of m6A demethylases. In addition, the use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrate that these enzymes modulate the expression of genes involved in pancreatic β-cell identity and glucose-stimulated insulin secretion. Our data suggest that environmental variations, such as glucose, control m6A methylation in pancreatic β cells, playing a key role in the control of gene expression and pancreatic β-cell functions. Our results highlight novel causes and new mechanisms potentially involved in type 2 diabetes physiopathology and may contribute to a better understanding of the etiology of this disease.

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

“…The N6-methyladenosine (m6A) RNA modification is essential during the embryonic development of various organs including human islet β cell homeostasis [ 190 , 191 , 192 , 193 ]. The use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrates that these enzymes modulate the expression of genes involved in pancreatic β cell identity and GSIS [ 192 ].…”

“…The N6-methyladenosine (m6A) RNA modification is essential during the embryonic development of various organs including human islet β cell homeostasis [ 190 , 191 , 192 , 193 ]. The use of siRNA and/or specific inhibitors against selected m6A enzymes demonstrates that these enzymes modulate the expression of genes involved in pancreatic β cell identity and GSIS [ 192 ]. Increased expression of m6A methylation upregulates the IGF-1/AKT/PDX-1 pathway in human β cells, which ultimately inhibits cell-cycle arrest and protects insulin secretion [ 190 ].…”

“…FTO-deficient Min6 cells exhibited decreased levels of INS1 mRNA [ 192 ]. In accordance, mRNA silencing of FTO in GRINCH (Glucose-Responsive Insulin-secreting C-peptide-modified Human proinsulin) clonal rat β cells showed a significant reduction in GSIS [ 198 ].…”

Milk exosomal microRNAs: friend or foe?—a narrative review

“…Thus, deficient MEX miR signaling during formula feeding may explain the significant exacerbation of FTO expression in blood mononuclear cells of formula-fed infants compared to breastfed infants (249,256). Increased expression of FTO is not only involved in the pathogenesis of obesity (236)(237)(238)(239)(240)(241) but also of T2DM (257)(258)(259). Notably, m6A mRNA methylation plays a key role in human β-cell biology in physiological states and in T2DM (260).…”

Peptides Targeting RNA m6A Methylations Influence the Viability of Cancer Cells

“…In parallel to the changes in m 6 A levels, expression levels of m 6 A methyltransferases (writers) and demethylases (erasers) also change appropriately in cancer cell lines tested. [10][11][12] N6-methylations in RNA are also recognized by m 6 A reader proteins leading to the regulation of cellular protein levels. [13] We find targeting m 6 A-modified mRNA a feasible approach to inhibit the binding of methyl readers and erasers, thus altering the expression of many oncoproteins and tumor suppressor proteins.…”