| First Author | Jacovetti C | Year | 2015 |
| Journal | Mol Endocrinol | Volume | 29 |
| Issue | 5 | Pages | 693-702 |
| PubMed ID | 25751313 | Mgi Jnum | J:231642 |
| Mgi Id | MGI:5771975 | Doi | 10.1210/me.2014-1299 |
| Citation | Jacovetti C, et al. (2015) Contribution of Intronic miR-338-3p and Its Hosting Gene AATK to Compensatory beta-Cell Mass Expansion. Mol Endocrinol 29(5):693-702 |
| abstractText | The elucidation of the mechanisms directing beta-cell mass regeneration and maintenance is of interest, because the deficit of beta-cell mass contributes to diabetes onset and progression. We previously found that the level of the microRNA (miRNA) miR-338-3p is decreased in pancreatic islets from rodent models displaying insulin resistance and compensatory beta-cell mass expansion, including pregnant rats, diet-induced obese mice, and db/db mice. Transfection of rat islet cells with oligonucleotides that specifically block miR-338-3p activity increased the fraction of proliferating beta-cells in vitro and promoted survival under proapoptotic conditions without affecting the capacity of beta-cells to release insulin in response to glucose. Here, we evaluated the role of miR-338-3p in vivo by injecting mice with an adeno-associated viral vector permitting specific sequestration of this miRNA in beta-cells. We found that the adeno-associated viral construct increased the fraction of proliferating beta-cells confirming the data obtained in vitro. miR-338-3p is generated from an intron of the gene coding for apoptosis-associated tyrosine kinase (AATK). Similarly to miR-338-3p, we found that AATK is down-regulated in rat and human islets and INS832/13 beta-cells in the presence of the cAMP-raising agents exendin-4, estradiol, and a G-protein-coupled Receptor 30 agonist. Moreover, AATK expression is reduced in islets of insulin resistant animal models and selective silencing of AATK in INS832/13 cells by RNA interference promoted beta-cell proliferation. The results point to a coordinated reduction of miR-338-3p and AATK under insulin resistance conditions and provide evidence for a cooperative action of the miRNA and its hosting gene in compensatory beta-cell mass expansion. |
