| First Author | Inada A | Year | 2023 |
| Journal | Am J Pathol | Volume | 193 |
| Issue | 8 | Pages | 1081-1100 |
| PubMed ID | 37516458 | Mgi Jnum | J:339009 |
| Mgi Id | MGI:7517807 | Doi | 10.1016/j.ajpath.2023.04.012 |
| Citation | Inada A, et al. (2023) Greb1 Transiently Accelerates Pancreatic beta-Cell Proliferation in Diabetic Mice Exposed to Estradiol. Am J Pathol 193(8):1081-1100 |
| abstractText | Decrease of pancreatic beta cells leads to diabetes. In an inducible cAMP early suppressor (ICER-Igamma) transgenic mouse model of severe type 2 diabetes with reduced insulin production and depleted beta cells, supplementation with high concentrations of 17beta-estradiol (E2) markedly enhances beta-cell proliferation and normalizes glucose levels. The current study explored the underlying mechanisms leading to a dynamic increase of beta cells and pathologic changes in diabetic mice exposed to E2. Gene expression profiling of pancreatic islets of 6-month-old ICER-transgenic mice recovering from diabetes due to elevated E2 levels identified growth regulation by estrogen in breast cancer 1 (Greb1) as a gene significantly up-regulated during the recovery phase. To substantiate this, beta-cell-specific Greb1-deficient mice were generated, and Greb1 was shown to be essential for recovery of depleted beta cells in diabetic mice. Graft growth and glucose lowering were observed in 50 islets with increased Greb1 expression transplanted adjacent to E2 pellets beneath the kidney capsule of streptozotocin-induced diabetic mice. Greb1 expression due to a drastic increase in exogenous or endogenous E2 was transient and closely correlated with changes in E2-related and some cell cycle-related genes. These findings provide new insights into in vivo proliferation of deficient beta cells and suggest the possibility of new therapeutic approaches targeting pancreatic beta cells that could revolutionize the concept of diabetes treatment, which has been considered difficult to cure completely. |
