β-Cell <i>miRNA-503-5p</i> Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and β-Cell Decompensation

Abstract

Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired β-cells release nanovesicular miR-503-5p to accumulate in liver and adipose tissue, leading to their insulin resistance via the miR-503-5p/insulin receptor/phosphorylated AKT axis. Accumulated miR-503-5p in β-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of β-cell miR-503-5p improves β-cell function and glucose tolerance in aging mice.