| First Author | Talchai SC | Year | 2015 |
| Journal | Diabetes | Volume | 64 |
| Issue | 8 | Pages | 2868-79 |
| PubMed ID | 25784544 | Mgi Jnum | J:246477 |
| Mgi Id | MGI:5924602 | Doi | 10.2337/db14-1696 |
| Citation | Talchai SC, et al. (2015) Legacy Effect of Foxo1 in Pancreatic Endocrine Progenitors on Adult beta-Cell Mass and Function. Diabetes 64(8):2868-79 |
| abstractText | beta-Cell dysfunction in diabetes results from abnormalities of insulin production, secretion, and cell number. These abnormalities may partly arise from altered developmental programming of beta-cells. Foxo1 is important to maintain adult beta-cells, but little is known about its role in pancreatic progenitor cells as determinants of future beta-cell function. We addressed this question by generating an allelic series of somatic Foxo1 knockouts at different stages of pancreatic development in mice. Surprisingly, ablation of Foxo1 in pancreatic progenitors resulted in delayed appearance of Neurogenin3(+) progenitors and their persistence into adulthood as a self-replicating pool, causing a fourfold increase of beta-cell mass. Similarly, Foxo1 ablation in endocrine progenitors increased their numbers, extended their survival, and expanded beta-cell mass. In contrast, ablation of Foxo1 in terminally differentiated beta-cells did not increase beta-cell mass nor did it affect Neurogenin3 expression. Despite the increased beta-cell mass, islets from mice lacking Foxo1 in pancreatic or endocrine progenitors responded poorly to glucose, resulting in glucose intolerance. We conclude that Foxo1 integrates cues that determine developmental timing, pool size, and functional features of endocrine progenitor cells, resulting in a legacy effect on adult beta-cell mass and function. Our results illustrate how developmental programming predisposes to beta-cell dysfunction in adults and raise questions on the desirability of increasing beta-cell mass for therapeutic purposes in type 2 diabetes. |
