<b>Beta-cell </b><b><i>MiRNA-503-5p</i></b><b> Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and β-Cell Decompensation</b>

<p dir="ltr"><b>ABSTRACT</b></p><p dir="ltr">Chronic 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 <i>miR-503-5p</i> 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 <i>miR-503</i> transgenic (βTG) mice display mild or severe diabetes in a time- and expression-dependent manner. By contrast, deletion of the <i>miR-503</i> cluster protects mice from high-fat-diet-induced insulin resistance and glucose intolerance. Mechanistically, <i>miR-503-5p</i> 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 <i>miR-503-5p</i> is packaged in nano-vesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin<i> </i>receptors (INSR). <a href="" target="_blank">Notably, specifically blocking the <i>miR-503</i> cluster in β cells effectively remits ageing-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our finding demonstrated that β-cell <i>miR-503-5p</i> is required for the development of insulin resistance and β-cell decompensation, providing a potential</a> therapeutic target against diabetes.</p>