The m6A Methyltransferase METTL3 Ameliorates Methylglyoxal-Induced Impairment of Insulin Secretion in Pancreatic β Cells by Regulating MafA Expression

Abstract

Methylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N6-methyladenosine (m6A), an RNA modification consisting of methylation at the N6 position of adenosine. However, the role of m6A methylation modification in methylglyoxal-induced impairment of insulin secretion in pancreatic β cells has not been clarified. In this study, we showed that treatment of two β-cell lines, NIT-1 and β-TC-6, with methylglyoxal reduced m6A RNA content and methyltransferase-like 3 (METTL3) expression levels. We also showed that silencing of METTL3 inhibited glucose-stimulated insulin secretion (GSIS) from NIT-1 cells, whereas upregulation of METTL3 significantly reversed the methylglyoxal-induced decrease in GSIS. The methylglyoxal-induced decreases in m6A RNA levels and METTL3 expression were not altered by knockdown of the receptor for the advanced glycation end product but were further decreased by silencing of glyoxalase 1. Mechanistic investigations revealed that silencing of METTL3 reduced m6A levels, mRNA stability, and the mRNA and protein expression levels of musculoaponeurotic fibrosarcoma oncogene family A (MafA). Overexpression of MafA greatly improved the decrease in GSIS induced by METTL3 silencing; silencing of MafA blocked the reversal of the MG-induced decrease in GSIS caused by METTL3 overexpression. The current study demonstrated that METTL3 ameliorates MG-induced impairment of insulin secretion in pancreatic β cells by regulating MafA.

Effect of lawsone‐preconditioned mesenchymal stem cells on the regeneration of pancreatic β cells in Type 1 diabetic rats

“…It is documented that diabetic rats display decreased levels of MafA 44,45 . Several other studies also report the increased expression MafA in treated rats compared with the diabetic rats 46–48 . Therefore, lawsone preconditioning appears to preferentially increase the expression of NGN3 and MafA compared with normal MSCs.…”

“…44,45 Several other studies also report the increased expression MafA in treated rats compared with the diabetic rats. [46][47][48] Therefore, lawsone preconditioning appears to preferentially increase the expression of NGN3…”

m6A mRNA methylation: Biological features, mechanisms, and therapeutic potentials in type 2 diabetes mellitus

“…26 In pancreatic β-cell, depletion of METTL3/14 suppresses glucose-stimulated insulin secretion and induces β-cell death. 24,165 Adipose-specific deficiency of the METTL3 gene cripples WAT beiging and reduces the metabolic capability in mice fed with HFD. 43 In hepatic tissue, METTL3 reduces hepatic insulin sensitivity via m 6 A modification of Fasn mRNA and enhancing fatty acid synthesis.…”

“…In neonatal murine β‐cells, METTL3/14 have been found to be dispensable for β‐cell differentiation, while they are essential for neonatal β‐cell maturation and mass establishment 26 . In pancreatic β‐cell, depletion of METTL3/14 suppresses glucose‐stimulated insulin secretion and induces β‐cell death 24,165 . Adipose‐specific deficiency of the METTL3 gene cripples WAT beiging and reduces the metabolic capability in mice fed with HFD 43 .…”

N-methyladenosine modification in ischemic stroke: Functions, regulation, and therapeutic potential

“…METTL3-deficient islet β cells have been found to be associated with islet β-cell failure and hyperglycemia, which could be attributed to a reduction in m 6 A levels mediated by METTL3 deficiency and reductions in the expression of genes involved in insulin secretion [ 68 ]. Furthermore, by modulating the stability and expression of MafA through m 6 A methylation, the expression of METTL3 has been shown to alleviate the impairment of methylglyoxal-induced insulin in β cells [ 69 ]. In addition to METTL3/14, other m 6 A regulators have also been implicated in DM.…”