| First Author | Zhou Y | Year | 2024 |
| Journal | Diabetes | Volume | 73 |
| Issue | 1 | Pages | 57-74 |
| PubMed ID | 37847900 | Mgi Jnum | J:344870 |
| Mgi Id | MGI:7579437 | Doi | 10.2337/db22-1044 |
| Citation | Zhou Y, et al. (2024) beta-Cell miRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and beta-Cell Decompensation. Diabetes 73(1):57-74 |
| abstractText | Chronic inflammation promotes pancreatic beta-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1beta (IL-1beta) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1beta levels. beta-Cell-specific miR-503 transgenic 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 c-Jun N-terminal kinase-interacting protein 2 (JIP2) translation to activate mitogen-activated protein kinase signaling cascades, thus inhibiting glucose-stimulated insulin secretion (GSIS) and compensatory beta-cell proliferation. In addition, beta-cell miR-503-5p is packaged in nanovesicles to dampen insulin signaling transduction in liver and adipose tissues by targeting insulin receptors. Notably, specifically blocking the miR-503 cluster in beta-cells effectively remits aging-associated diabetes through recovery of GSIS capacity and insulin sensitivity. Our findings demonstrate that beta-cell miR-503-5p is required for the development of insulin resistance and beta-cell decompensation, providing a potential therapeutic target against diabetes. ARTICLE HIGHLIGHTS: Promoter hypomethylation during natural aging permits miR-503-5p overexpression in islets under inflammation conditions, conserving from rodents to humans. Impaired beta-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 beta-cells impairs glucose-stimulated insulin secretion via the JIP2-coordinated mitogen-activated protein kinase signaling cascades. Specific blockage of beta-cell miR-503-5p improves beta-cell function and glucose tolerance in aging mice. |
