| First Author | Oliveira JM | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 306 |
| Issue | 1 | Pages | E36-47 |
| PubMed ID | 24253047 | Mgi Jnum | J:208382 |
| Mgi Id | MGI:5562995 | Doi | 10.1152/ajpendo.00409.2013 |
| Citation | Oliveira JM, et al. (2014) Tungstate promotes beta-cell survival in Irs2-/- mice. Am J Physiol Endocrinol Metab 306(1):E36-47 |
| abstractText | Pancreatic beta-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional beta-cell mass that is associated mainly with increased beta-cell apoptosis. Thus, understanding how to enhance survival of beta-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in beta-cells. In fact, IRS-2 is critically required for beta-cell compensation in conditions of increased insulin demand and for beta-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote beta-cell recovery in toxin-induced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive beta-cell death. To this end, we treated mice deficient in IRS2 (Irs2(-/-)), which exhibit severe beta-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2(-/-) mice in correlation with increased beta-cell mass, increased beta-cell replication, and a striking threefold reduction in beta-cell apoptosis. Islets from treated Irs2(-/-) exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2(-/-) islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2(-/-) mice, consistent with reduced apoptotic rates. Our results support the finding that beta-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing beta-cell mass decline are potential strategies to prevent the progression to T2D. |
