NR3C1/Glucocorticoid receptor activation promotes pancreatic β-cell autophagy overload in response to glucolipotoxicity

Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic β-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of β-cells, whereas excessive autophagy is also involved in β-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in β-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in β-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the N6-methyladenosine (m6A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in β-cells, which caused diminished m6A modifications on mRNAs of four core Atg (autophagy related) genes (Atg12, Atg5, Atg16l2, Atg9a) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic β-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m6A modifications-Atg genes axis acts as a key mediator of balanced autophagic flux in pancreatic β-cells, which offers a novel therapeutic target for the treatment of diabetes.