Β-Cell Mirna-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and Β-Cell Decompensation.

ABSTRACTChronic inflammation promotes pancreatic β-cell decompensation to insulin resistance due to local accumulation of supraphysiologic IL-1β levels. However, the underlying molecular mechanism(s) remains elusive. We show that miR-503-5p is exclusively upregulated in islets from type 2 diabetic humans and rodents due to its promoter hypomethylation and increased local IL-1β levels. Beta-cell-specific miR-503 transgenic (βTG) mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the miR-503 cluster protects mice from high-fat-diet-induced insulin resistance and glucose intolerance. Mechanistically, miR-503-5p represses JNK interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinases (MAPKs) signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory β-cell proliferation. In addition, β-cell miR-503-5p is packaged in nano-vesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors (INSR). Notably, specifically blocking the miR-503 cluster in β cells effectively remits ageing-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our finding demonstrated that β-cell miR-503-5p is required for the development of insulin resistance and β-cell decompensation, providing a potential therapeutic target against diabetes.